DE60129442T2 - Sulphonic acid derivates of hydroxyacrylic acids and their use in medicinal products - Google Patents

Abstract

The present invention relates to a novel sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof. More particularly, the present invention relates to a sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof, which is useful as an inhibitor of lipopolysaccharides (LPS). In addition, the present invention relates to a novel intermediate compound useful for the synthesis of this sulfonic acid derivative of hydroxamic acid.

Description

Technical area

The The present invention relates to a novel sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof. In particular, it concerns the present invention, a sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof which is used as an inhibitor of Lipopolysaccharide (LPS) is useful. Furthermore, the concerns present invention provides a novel intermediate for use in synthesis of the above sulfonic acid derivative of hydroxamic acid is usable.

State of the art

sepsis is a systemic inflammatory reaction syndrome defined in connection with an infection [R. C. Bone: Ann. Intern. Med. 115, 457 (1991)] and initially begins with excessive invasion of Gram-negative bacteria, the causative bacteria for sepsis are, or an endotoxin, which is a basic component from the cell wall, from a primary lesion into the blood and its Distribution within the body by means of the cycle. The endotoxin is an in the outer bacterial membrane lipopolysaccharide (LPS) present as a result of the death of Gram-negative bacteria is released. It stimulates inflammatory cells like macrophages, the neutrophils, lymphocytes and the like and the vascular endothelial cell in organisms, causing formation of inflammatory cytokines (IL-1, IL-6, IL-8 and the like) inclusive TNF α (tumor necrosis factor α) causes becomes. Such a remarkable increase in inflammatory cytokines causes Severe multiple organ failure (MODS) often leads to the death of organisms.

at The chemotherapy of sepsis is essentially the first use of antibiotics required for the destruction of infectious bacteria. In general, administration of antibiotics is the most common with regard to the high probability of subsequent complications in parallel with chemo or surgical treatment of Complications [Fujii et al., Pharmaceutical Agent Journal, 34, 1501 (1998)]. As it follows that the lethality due to from sepsis since the 80s of the 20th century not decreased However, it is believed that these treatments their Reached the limit.

In In recent years, anti-cytokine therapies are on an attack on inflammatory cytokines like TNF α and such as a novel method of treating sepsis been actively tried. Their effectiveness in clinical trials TNF α neutralizing Antibody, a soluble TNF-α receptor and However, an IL-1 receptor antagonist and the like could not confirmed [Gou Wakabayashi et al., Igaku no Ayumi Bessatsu, 108 (1998)]. It is believed that the target inflammatory cytokine is harmful, if it's in excess exists, but for a biological protection is necessary, as long as it is in a particular Quantity is generated.

This means a complete control of the biological activity of cytokine reversed the lesion dependent on worsen the stages of the disease state of sepsis patients can, which is believed to be in this clinical Achievements [Masahiko Hirota et al., Nihon Gekagakkai Zasshi 100: 667-673 (1999), Gou Wakabayashi et al., Nihon Gekagakkai Zasshi 100: 674-678 (1999)].

Furthermore is the medicine-developed column for the removal of endotoxin, although confirmed has been clinically effective [Kazuhiko Hanazawa et al., ICU and CCU, 197 (1999)], expensive, and their use within of the framework that insurance policies can cover is limited. The above lets the Importance of endotoxin in the disease state of sepsis and teaches that a low-molecular compound, the endotoxin as such, upstream of various inflammatory cytokines including TNF α inhibits, a promising new means of prophylaxis or treatment of sepsis is.

Heretofore, hydroxamic acid derivatives have been studied as inhibitors of matrix metalloproteinase (MMP), and it has been reported that many such inhibitors have an inhibitory effect on inflammatory cytokines, particularly TNFα. Many of them have been studied as agents for the prophylaxis or treatment of sepsis (eg WO94 / 10990 etc.), but have not been clinically used. In addition, an endotoxin (LPS) inhibitory effect of hydroxamic acid derivatives has not previously been reported.

EP-1 081 132 discloses hydroxamic acid derivatives or pharmacologically acceptable salts thereof exemplified by the general formula (I), medicinal compositions containing them, and a use thereof in medicine, each symbol having the meaning as defined in the application. Because these derivatives or pharmacologically acceptable salts thereof have an inhibitory effect on the formation of TNF-α, they are for the prevention / treatment of autoimmune diseases and inflammatory diseases, for example, sepsis, MOF, rheumatoid arthritis, Crohn's disease, cachexia, myastenia gravis, systemic lupus erythematosus, asthma, type I diabetes and psoriasis.

The The present invention is in view of the above-mentioned prior art The technique has been made and aims to provide a new sulfonic acid derivative of hydroxamic acid available which is useful as an LPS inhibitor, and a pharmacological acceptable salt thereof available close.

A Another object of the present invention is to provide a new intermediate used to synthesize the compound is usable.

Yet Another object of the present invention is to provide a new LPS inhibitor useful as a pharmaceutical.

Disclosure of the invention

The Inventors of the present invention have found that a sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof, inhibiting LPS Has effect, and furthermore they have found that connection the present invention, an increase of LPS also in animal Models inhibiting what to complete the present invention guided Has.

• (1) Sulfonsäurederivat von Hydroxamsäure der Formel (I)
  
  wobei X Wasserstoff oder eine hydroxylgruppenschützende Gruppe ist, R¹ Wasserstoff, ein lineares oder verzweigtes Alkyl mit 1 bis 10 Kohlenstoffatomen, ein Arylalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroarylalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein orthokondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroarylalkylthioalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein ortho-kondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatome hat und der Thioalkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroarylthioalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein ortho-kondensiertes, heterocyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Thioalkylrest 1 bis 6 Kohlenstoffatome hat, ein Arylthioalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Thioalkylrest 1 bis 6 Kohlenstoffatome hat, ein Alkylthioalkyl, wobei der Alkylthiorest 1 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Arylalkylthioalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat und der Thioalkylrest 1 bis 6 Kohlenstoffatome hat, ein Phthaloimidoalkyl, wobei der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Alkenyl mit 2 bis 6 Kohlenstoffatomen oder -(CH₂)_l-A ist [wobei l eine ganze Zahl von 1 bis 4 ist und A ein stickstoffhaltiger 5- oder 6-gliedriger Heteroring ist, der (a) über ein Stickstoffatom gebunden ist, (b) gegebenenfalls als weiteres Heteroatom wenigstens eine Art eines aus Stickstoff, Sauerstoff und Schwefel ausgewählten Atoms in einer Position umfasst, die zum gebundenen Stickstoffatom nicht benachbart ist, (c) zum gebundenen Stickstoffatom nachbarständige Kohlenstoffatome umfasst, wobei ein oder beide davon durch Oxo substituiert sind und der (d) benzokondensiert ist oder ein oder mehrere weitere Kohlenstoffatome hat, die gegebenenfalls durch ein lineares oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen oder Oxo substituiert sind, und/oder der ein weiteres Stickstoffatom hat, das gegebenenfalls durch ein lineares oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen oder Phenyl substituiert ist], R² Wasserstoff, ein lineares oder verzweigtes Alkyl mit 1 bis 10 Kohlenstoffatomen, ein Arylalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroarylalkyl, wobei der Heteroarylrest eine 5- bis 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein orthokondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Cycloalkyl mit 3 bis 7 Kohlenstoffatomen, ein Cycloalkylalkyl, wobei der Cycloalkylrest 3 bis 7 Kohlenstoffatome und der Alkylrest 1 bis 6 Kohlenstoffatome hat, oder ein Aryl mit 6 bis 10 Kohlenstoffatomen ist, Y O, NR⁷ (wobei R⁷ der Definition von R² entspricht) oder S ist, n eine ganze Zahl von 1 bis 6 ist, R³ Wasserstoff, ein Halogen (Fluor, Chlor, Brom, Iod), eine Hydroxylgruppe, Trifluormethyl, Cyan, Nitro, Amino, ein lineares oder verzweigtes Alkyl mit 1 bis 10 Kohlenstoffatomen, ein lineares oder verzweigtes Alkoxy mit 1 bis 6 Kohlenstoffatomen, ein lineares oder verzweigtes Alkanoyloxy mit 2 bis 6 Kohlenstoffatomen, Carbamoyl, eine C_1-6-Alkylamino- oder Di-C_1-6-Alkylaminogruppe ist, R⁴ OR⁸ (wobei R⁸ Wasserstoff, ein lineares oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen, ein Aryl mit 6 bis 10 Kohlenstoffatomen, ein Heteroaryl, ausgewählt aus einer 5- oder 6-gliedrigen Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein orthokondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, und ein N-Oxid davon, ein Arylalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, oder ein Heteroarylalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein ortho-kondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatom hat) oder NR¹⁰R¹¹ [wobei R¹⁰ und R¹¹ gleich oder verschieden sind und jeweils Wasserstoff, ein lineares oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen, ein Arylalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroaryl, das aus einer 5- oder 6-gliedrigen Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff) ausgewählt ist, ein orthokondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, und ein N-Oxid davon, ein Heteroarylalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff) ist, ein ortho-kondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatome hat oder ein Aryl mit 6 bis 10 Kohlenstoffatomen ist oder R¹⁰ und R¹¹ gegebenenfalls zusammen mit dem benachbarten Stickstoffatom einen gegebenenfalls substituierten Heteroring bilden, sind] ist und wobei das Arylalkyl, Heteroarylalkyl, Heteroarylalkylthioalkyl, Heteroarylthioalkyl, Arylthioalkyl, Arylalkylthioalkyl, Phthaloimidoalkyl, Aryl und Heteroaryl, die alle wie oben definiert sind, gegebenenfalls einen oder mehrere Substituenten haben, die aus einem Halogen, einer Hydroxylgruppe, Nitro, Cyan, Trifluormethyl, einem C_1-6-Alkyl, C_1-6-Alkoxy, C_1-6-Alkylthio, Formyl, einem C_1-6-Alkanoyloxy, Oxo, Phenyl, einem oben definierten Arylalkyl, Carboxyl, einer durch -COOR_a veranschaulichten Gruppe [wobei R_a ein C_1-6-Alkyl, ein oben definiertes Arylalkyl oder ein C_6-10-Aryl ist], Carbamoyl, Amino, einem C_1-6-Alkylamino, einem Di-C_1-6-Alkylamino, Guanidino, Hydroxysulfonyloxy, Arylalkyloxyalkyl, wobei der Arylalkylrest oben definiert ist und der Oxyalkylrest 1 bis 6 Kohlenstoffatome hat, ausgewählt sind, oder ein pharmakologisch annehmbares Salz davon.
• (2) Sulfonsäurederivat von Hydroxamsäure nach (1), wobei R³ Wasserstoff ist, oder ein pharmakologisch annehmbares Salz davon.
• (3) Sulfonsäurederivat von Hydroxamsäure nach (1) oder (2), wobei R⁴ NHCH₃ oder NHC₆H₅ ist, oder ein pharmakologisch annehmbares Salz davon.
• (4) Sulfonsäurederivat von Hydroxamsäure nach einem von (1) bis (3), wobei R¹ Phthaloimidomethyl ist, oder ein pharmakologisch annehmbares Salz davon.
• (5) Sulfonsäurederivat von Hydroxamsäure nach einem von (1) bis (4), wobei R² Isobutyl ist, oder ein pharmakologisch annehmbares Salz davon.
• (6) Sulfonsäurederivat von Hydroxamsäure, ausgewählt aus der Gruppe bestehend aus 5-Methyl-3(R)-[1(S)-methylcarbamoyl-2-(4-sulfomethoxyphenyl)ethylcarbamoyl]-2(R oder S)-phthalimidomethylhexanohydroxamsäure, 5-Methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(2-sulfoethoxy)phenylmethylcarbamoyl}-2(R oder S)-phthalimidomethylhexanohydroxamsäure, 5-Methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(R oder S)-phthalimidomethylhexanohydroxamsäure, 5-Methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(4-sulfobutoxy)phenyl]ethylcarbamoyl}-2(R oder S)-phthalimidomethylhexanohydroxamsäure, 5-Methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(5-sulfopentoxy)phenyl]ethylcarbamoyl}-2(R oder S)-phthalimidomethylhexanohydroxamsäure, 5-Methyl-3(R)-[1(S)-methylcarbamoyl-2-(4-sulfomethoxyphenyl)ethylcarbamoyl]-2(R oder S)-(2-naphthylmethyl)hexanohydroxamsäure, 5-Methyl-3(R)-{1(S)-methylcarbamoyl-2-(4-(2-sulfoethoxy)phenyl]ethylcarbamoyl}-2(R oder S)-(2-naphthylmethyl)hexanohydroxamsäure, 5-Methyl-3(R)-(1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl)-2(R oder S)-(2-naphthylmethyl)hexanohydroxamsäure, 5-Methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(4-sulfobutoxy)phenyl]ethylcarbamoyl}-2(R oder S)-(2-naphthylmethyl)hexanohydroxamsäure, 5-Methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(5-sulfopentoxy)phenyl]ethylcarbamoyl}-2(R oder S)-(2-naphthylmethyl)hexanohydroxamsäure, 5-Methyl-3(R)-{1(S)-phenylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(R oder S)-phthalimidomethylhexanohydroxamsäure, oder ein pharmakologisch annehmbares Salz davon.
• (7) Verbindung der Formel (III)
  
  wobei R⁹ Wasserstoff, ein lineares oder verzweigtes Alkyl mit 1 bis 10 Kohlenstoffatomen, ein Arylalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroarylalkyl ist, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein orthokondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatome hat oder ein Aryl mit 6 bis 10 Kohlenstoffatomen ist,
  
  eine Einfachbindung oder Doppelbindung ist, R¹³ wenn
  
  eine Einfachbindung ist, Wasserstoff, ein Alkyl, ein lineares oder verzweigtes Alkyl mit 1 bis 10 Kohlenstoffatomen, ein Arylalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroarylalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein ortho-kondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon stammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroarylalkylthioalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein ortho-kondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon stammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatome hat und der Thioalkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroarylthioalkyl, wobei der Heteroarylrest eine 5- bis 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein ortho-kondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon stammt, oder ein N-Oxid davon ist und der Thioalkylrest 1 bis 6 Kohlenstoffatome hat, ein Arylthioalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Thioalkylrest 1 bis 6 Kohlenstoffatome hat, ein Alkylthioalkyl, wobei der Alkylthiorest 1 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Arylalkylthioalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat und der Thioalkylrest 1 bis 6 Kohlenstoffatome hat, ein Phthaloimidoalkyl, wobei der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Alkenyl mit 2 bis 6 Kohlenstoffatomen, -(CH2)_l-A [wobei l eine ganze Zahl von 1 bis 4 ist und A ein stickstoffhaltiger 5- oder 6-gliedriger Heteroring ist, der (a) über ein Stickstoffatom gebunden ist, (b) gegebenenfalls als weiteres Heteroatom wenigstens eine Art eines aus Stickstoff, Sau erstoff und Schwefel ausgewählten Atoms in einer Position umfasst, die zum gebundenen Stickstoffatom nicht benachbart ist, (c) zum gebundenen Stickstoffatom nachbarständige Kohlenstoffatome umfasst, wobei ein oder beide davon durch Oxo substituiert sind und der (d) benzokondensiert ist oder ein oder mehrere weitere Kohlenstoffatome hat, die gegebenenfalls durch ein lineares oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen oder Oxo substituiert sind, und/oder der ein weiteres Stickstoffatom hat, das gegebenenfalls durch ein lineares oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen oder Phenyl substituiert ist] oder -COOR¹⁴ (wobei R¹⁴ Wasserstoff, ein lineares oder verzweigtes Alkyl mit 1 bis 10 Kohlenstoffatomen, ein Arylalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroarylalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein ortho-kondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatome oder ein Aryl mit 6 bis 10 Kohlenstoffatomen ist) oder CH₂ ist, wenn
  
  eine Doppel bindung ist, R² Wasserstoff, ein lineares oder verzweigtes Alkyl mit 1 bis 10 Kohlenstoffatomen, ein Arylalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroarylalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein orthokondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Cycloalkyl mit 3 bis 7 Kohlenstoffatomen, ein Cycloalkylalkyl, wobei der Cycloalkylrest 3 bis 7 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, oder ein Aryl mit 6 bis 10 Kohlenstoffatomen ist, Y O, NR⁷ (wobei R⁷ wie für R₂ definiert ist) oder S ist, n eine ganze Zahl von 1 bis 6 ist, R³ Wasserstoff, ein Halogen (Fluor, Chlor, Brom, Iod), eine Hydroxylgruppe, Trifluormethyl, Cyan, Nitro, Amino, ein lineares oder verzweigtes Alkyl mit 1 bis 10 Kohlenstoffatomen, ein lineares oder verzweigtes Alkoxy mit 1 bis 6 Kohlenstoffatomen, ein lineares oder verzweigtes Alkanoyloxy mit 2 bis 6 Kohlenstoffatomen, Carbamoyl, eine C_1-5-Alkylamino- oder Di-C_1-6-Alkylaminogruppe ist, und R⁴ OR⁸ (wobei R⁸ Wasserstoff, ein lineares oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen, ein Aryl mit 6 bis 10 Kohlenstoffatomen, ein Heteroaryl, ausgewählt aus einer 5- oder 6-gliedrigen Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein orthokondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, und ein N-Oxid davon, ein Arylalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, oder ein Heteroarylalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff), ein ortho-kondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatom hat) oder NR¹⁰R¹¹ wobei R¹⁰ und R¹¹ gleich oder verschieden sind und jeweils Wasserstoff, ein lineares oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen, ein Arylalkyl, wobei der Arylrest 6 bis 10 Kohlenstoffatome hat und der Alkylrest 1 bis 6 Kohlenstoffatome hat, ein Heteroaryl, das aus einer 5- oder 6-gliedrigen Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff) ausgewählt ist, ein orthokondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, und ein N-Oxid davon, ein Heteroarylalkyl, wobei der Heteroarylrest eine 5- oder 6-gliedrige Ringgruppe mit einem Kohlenstoffatom und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff) ist, ein ortho-kondensiertes, bicyclisches Heteroaryl mit 8 bis 10 Ringatomen, das davon abstammt, oder ein N-Oxid davon ist und der Alkylrest 1 bis 6 Kohlenstoffatome hat oder ein Aryl mit 6 bis 10 Kohlenstoffatomen ist oder R¹⁰ und R¹¹ gegebenenfalls zusammen mit dem benachbarten Stickstoffatom einen gegebenenfalls substituierten Heteroring bilden, sind] ist oder ein pharmakologisch annehmbares Salz davon.
• (8) Pharmazeutische Zusammensetzung, umfassend das Sulfonsäurederivat von Hydroxamsäure nach einem von (1) bis (6) oder ein pharmakologisch annehmbares Salz davon und einen pharmakologisch annehmbaren Träger.
• (9) LPS-Inhibitor, umfassend das Sulfonsäurederivat von Hydroxamsäure nach einem von (1) bis (6) oder ein pharmakologisch annehmbares Salz davon als Wirkstoff.
• (10) Mittel zur Prophylaxe oder Behandlung von Sepsis, MOF, chronischem Gelenkrheumatismus, Morbus Crohn, Kachexie, Myasthenia gravis, systemischem Lupus erythematodes, Asthma, Typ-I-Diabetes oder Psoriasis, umfassend das Sulfonsäurederivat von Hydroxamsäure nach einem von (1) bis (6) oder ein pharmakologisch annehmbares Salz davon als Wirkstoff.

Accordingly, the present invention provides the following.

• (1) Sulfonic acid derivative of hydroxamic acid of the formula (I)
  
  wherein X is hydrogen or a hydroxyl group-protecting group, R ^{1 is} hydrogen, a linear or branched alkyl having 1 to 10 carbon atoms, an arylalkyl, wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms, a heteroarylalkyl, wherein the heteroaryl group a 5- or 6-membered ring group having a carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group 1 to 6 carbon atoms, a heteroarylalkylthioalkyl wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms thereof or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms and the thioalkyl group has 1 to 6 carbon atoms e has, a heteroarylthioalkyl wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused heterocyclic heteroaryl having 8 to 10 ring atoms derived therefrom, or an N-oxide thereof and the thioalkyl group has 1 to 6 carbon atoms, an arylthioalkyl wherein the aryl group has 6 to 10 carbon atoms and the thioalkyl group has 1 to 6 carbon atoms, an alkylthioalkyl wherein the alkylthio group has 1 to 10 carbon atoms and the alkyl group Has 1 to 6 carbon atoms, an arylalkylthioalkyl wherein the aryl radical has 6 to 10 carbon atoms and the alkyl radical has 1 to 6 carbon atoms and the thioalkyl radical has 1 to 6 carbon atoms, a phthaloimidoalkyl wherein the alkyl radical has 1 to 6 carbon atoms, an alkenyl with 2 to 6 carbon atoms or - (CH ₂ ) ₁ -A- [wherein l is an integer from 1 to 4 and A is a nitrogen-containing 5- or 6-membered (b) optionally, as another heteroatom, it comprises at least one kind of atom selected from nitrogen, oxygen and sulfur in a position not adjacent to the bonded nitrogen atom, (c) the hetero ring which is (a) linked through a nitrogen atom; bonded nitrogen atom comprises adjacent carbon atoms, one or both of which are substituted by oxo and (d) is benzo-fused or has one or more other carbon atoms optionally substituted by a linear or branched alkyl of 1 to 6 carbon atoms or oxo, and / or having another nitrogen atom optionally substituted by a linear or branched alkyl substituted with 1 to 6 carbon atoms or phenyl], R ^{2 is} hydrogen, a linear or branched alkyl having 1 to 10 carbon atoms, an arylalkyl, wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms, a heteroarylalkyl, wherein the heteroaryl group is a 5- to 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, or an N-oxide thereof and the Alkyl radical has 1 to 6 carbon atoms, a cycloalkyl having 3 to 7 carbon atoms, a cycloalkylalkyl, wherein the cycloalkyl radical 3 to 7 carbon atoms and the alkyl radical has 1 to 6 carbon atoms, or is an aryl having 6 to 10 carbon atoms, Y is O, NR ⁷ (wherein R ⁷ corresponds to the definition of R ² ) or S, n is an integer from 1 to 6 R ^{3 is} hydrogen, a halogen (fluoro, chloro, bromo, iodo), a hydroxyl group, trifluoromethyl, cyano, nitro, amino, a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched alkoxy of 1 to 6 carbon atoms is a linear or branched alkanoyloxy having 2 to 6 carbon atoms, carbamoyl, a C _1-6 alkylamino or di C _1-6 alkylamino group, R ⁴ OR ⁸ (wherein R ^{8 is} hydrogen, a linear or branched alkyl having 1 to 6 carbon atoms, an aryl having 6 to 10 carbon atoms, a heteroaryl selected from a 5- or 6-membered ring group having a carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 Ring atoms, the d avon, and an N-oxide thereof, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms, or a heteroarylalkyl wherein the heteroaryl group has a 5 or 6 membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms) or NR ¹⁰ R ¹¹ [ wherein R ¹⁰ and R ^{11 are the} same or different and each is hydrogen, a linear or branched alkyl of 1 to 6 carbon atoms, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms, a heteroaryl consisting of a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ringat omen derived therefrom and an N-oxide thereof, a heteroarylalkyl wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic Heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms or is an aryl having 6 to 10 carbon atoms or R ¹⁰ and R ¹¹ optionally together with the adjacent nitrogen atom is optionally substituted Hetero ring are] and wherein the arylalkyl, heteroarylalkyl, heteroarylalkylthioalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl, phthaloimidoalkyl, aryl and heteroaryl, all as defined above, optionally have one or more substituents selected from a halogen, a hydroxyl group, nitro , Cyano, trifluoromethyl, a C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, formyl, a C _1-6 alkanoyloxy, O xo, phenyl, arylalkyl as defined above, carboxyl, a illustrated by -COOR _a group [where R _a is C _1-6 alkyl, an arylalkyl as defined above, or a C _6-10 aryl], carbamoyl, amino, C _1-6 alkylamino, di-C _1-6 alkylamino, guanidino, hydroxysulfonyloxy, arylalkyloxyalkyl wherein the arylalkyl radical is defined above and the oxyalkyl radical has 1 to 6 carbon atoms, or a pharmacologically acceptable salt thereof.
• (2) Sulfonic acid derivative of hydroxamic acid according to (1), wherein R ^{3 is} hydrogen, or a pharmacologically acceptable salt thereof.
• (3) Sulfonic acid derivative of hydroxamic acid according to (1) or (2), wherein R ^{4 is} NHCH ₃ or NHC ₆ H ₅ , or a pharmacologically acceptable salt thereof.
• (4) The sulfonic acid derivative of hydroxamic acid according to any one of (1) to (3), wherein R ^{1 is} phthaloimidomethyl, or a pharmacologically acceptable salt thereof.
• (5) The sulfonic acid derivative of hydroxamic acid according to any one of (1) to (4), wherein R ^{2 is} isobutyl, or a pharmacologically acceptable salt thereof.
• (6) Sulfonic acid derivative of hydroxamic acid selected from the group consisting of 5-methyl-3 (R) - [1 (S) -methylcarbamoyl-2- (4-sulfomethoxyphenyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid, 5 -Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (2-sulfoethoxy) phenylmethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid, 5-methyl-3 (R) - {1 ( S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimi domethylhexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (4-sulfobutoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid, 5-methyl-3 (R. ) - {1 (S) -methylcarbamoyl-2- [4- (5-sulfopentoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid, 5-methyl-3 (R) - [1 (S) -methylcarbamoyl -2- (4-sulfomethoxyphenyl) ethylcarbamoyl] -2 (R or S) - (2-naphthylmethyl) hexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- (4- (2- sulfoethoxy) phenyl] ethylcarbamoyl} -2 (R or S) - (2-naphthylmethyl) hexanohydroxamic acid, 5-methyl-3 (R) - (1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl) -2 (R or S) - (2-naphthylmethyl) hexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (4-sulfobutoxy) phenyl] ethylcarbamoyl} -2 (R or S) - (2-naphthylmethyl) hexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (5-sulfopentoxy) phenyl] ethylcarbamoyl} -2 (R or S ) - (2-naphthylmethyl) hexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -phenylcarbamoyl-2- [4- (3-sulfopropox y) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid, or a pharmacologically acceptable salt thereof.
• (7) Compound of the formula (III)
  
  wherein R ^{9 is} hydrogen, a linear or branched alkyl of 1 to 10 carbon atoms, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms is a heteroarylalkyl, wherein the heteroaryl group is a 5- or 6-membered one Ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms or an aryl with 6 to 10 carbon atoms,
  
  is a single bond or double bond, R ¹³ if
  
  a single bond is hydrogen, an alkyl, a linear or branched alkyl of 1 to 10 carbon atoms, an arylalkyl wherein the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, a heteroarylalkyl wherein the heteroaryl moiety is a 5- or 5-carbon A 6-membered ring group having a carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group is 1 to 6 Has carbon atoms, a heteroarylalkylthioalkyl wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms and the thioalkyl group has 1 to 6 carbon atoms, a heteroarylthioalkyl, wherein de r heteroaryl group is a 5- to 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, or an N-oxide thereof and the thioalkyl group has 1 to 6 carbon atoms, an arylthioalkyl wherein the aryl group has 6 to 10 carbon atoms and the thioalkyl group has 1 to 6 carbon atoms, an alkylthioalkyl wherein the alkylthio group has 1 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms Arylalkylthioalkyl wherein the aryl radical has 6 to 10 carbon atoms and the alkyl radical has 1 to 6 carbon atoms and the thioalkyl radical has 1 to 6 carbon atoms, a phthaloimidoalkyl wherein the alkyl radical has 1 to 6 carbon atoms, an alkenyl having 2 to 6 carbon atoms, - (CH 2 ) _l -A [wherein l is an integer from 1 to 4 and A is a nitrogen-containing 5- or 6-membered hetero ring which (a) bonds via a nitrogen atom (b) optionally, as another heteroatom, at least one type of atom selected from nitrogen, oxygen, and sulfur in a position not adjacent to the attached nitrogen atom, (c) having carbon atoms attached to the attached nitrogen atom, one or both of them of which are substituted by oxo and (d) is benzo-fused or has one or more other carbon atoms optionally substituted by a linear or branched alkyl of 1 to 6 carbon atoms atoms or oxo, and / or has another nitrogen atom, which is optionally substituted by a linear or branched alkyl having 1 to 6 carbon atoms or phenyl] or -COOR ¹⁴ (wherein R ^{14 is} hydrogen, a linear or branched alkyl having 1 to 10 carbon atoms, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms, a heteroarylalkyl wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group is 1 to 6 carbon atoms or an aryl having 6 to 10 carbon atoms) or CH ₂ , if
  
  a double bond, R ^{2 is} hydrogen, a linear or branched alkyl of 1 to 10 carbon atoms, an arylalkyl wherein the aryl radical has 6 to 10 carbon atoms and the alkyl radical has 1 to 6 carbon atoms, a heteroarylalkyl, wherein the heteroaryl radical is a 5- or A 6-membered ring group having a carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms , a cycloalkyl having 3 to 7 carbon atoms, a cycloalkylalkyl wherein the cycloalkyl group has 3 to 7 carbon atoms and the alkyl group has 1 to 6 carbon atoms, or an aryl having 6 to 10 carbon atoms, YO, NR ⁷ (wherein R ^{7 is} as for R _{2 is} defined) or S is, n is an integer from 1 to 6, R ^{3 is} hydrogen, a halogen (fluorine, chlorine, bromine, iodine), a hydroxyl group, trifluoromethyl, cyano, nitro, amino, a linear s or branched alkyl having 1 to 10 carbon atoms, a linear or branched alkoxy having 1 to 6 carbon atoms, a linear or branched alkanoyloxy having 2 to 6 carbon atoms, carbamoyl, a C _1-5 -alkylamino or Di-C _1-6 - Alkylamino group, and R ^{4 is} OR ⁸ (wherein R ^{8 is} hydrogen, a linear or branched alkyl of 1 to 6 carbon atoms, an aryl of 6 to 10 carbon atoms, a heteroaryl selected from a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, and an N-oxide thereof, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group 1 to Has 6 carbon atoms, or a heteroarylalkyl, wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-condensation r, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms) or NR ¹⁰ R ¹¹ wherein R ¹⁰ and R ^{11 are the} same or different and each is hydrogen, a linear or branched alkyl having 1 to 6 carbon atoms, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms, a heteroaryl consisting of a 5 or 6 membered ring group having one carbon atom and 1 to 4 Heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, and an N-oxide thereof, a heteroarylalkyl, wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, or an N-oxide thereof is un d is the alkyl group having 1 to 6 carbon atoms or is an aryl having 6 to 10 carbon atoms or R ¹⁰ and R ¹¹ optionally together with the adjacent nitrogen atom form an optionally substituted hetero ring are] or a pharmacologically acceptable salt thereof.
• (8) A pharmaceutical composition comprising the sulfonic acid derivative of hydroxamic acid according to any one of (1) to (6) or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier.
• (9) The LPS inhibitor comprising the sulfonic acid derivative of hydroxamic acid according to any one of (1) to (6) or a pharmacologically acceptable salt thereof as an active ingredient.
• (10) Agents for the prophylaxis or treatment of sepsis, MOF, chronic articular rheumatism, Crohn's disease, cachexia, myasthenia gravis, systemic lupus erythematosus, asthma, type I diabetes or psoriasis comprising the sulfonic acid derivative of hydroxamic acid according to any one of (1) to (1) (6) or a pharmacologically acceptable salt thereof as an active ingredient.

Best mode to run the invention

The Symbols used in the present description will be described below explained.

The "alkyl" for R ¹ , R ² , R ³ , R ⁷ , R ⁹ , R ¹³ and R ¹⁴ is a linear or branched alkyl having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-octyl, n-decyl and the like.

The "lower alkyl" for R ³ , R ⁶ , R ⁸ , R ¹⁰ and R ¹¹ is a linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Butyl, tert -butyl, n -pentyl, isopentyl, n -hexyl and the like.

The "aryl" for R ² , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹⁴ is an aryl having 6 to 10 carbon atoms, such as phenyl, naphthyl, an aryl which is is an ortho-fused bicyclic group having 8 to 10 ring atoms, wherein at least one ring is an aromatic ring (eg, indenyl and the like) and the like, with phenyl being preferred.

The "heteroaryl" for R ⁶ , R ⁸ , R ¹⁰ and R ¹¹ is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an 8 to 8 ortho-fused bicyclic heteroaryl 10 ring atoms derived therefrom, particularly a benzo derivative condensed with a benzene ring, one derived therefrom by condensing a propenylene, trimethylene or tetramethylene group therewith, a stable N-oxide thereof and the like. Examples thereof include pyrrolyl, pyrrolinyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl, 1 , 2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1 , 3,5-triazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, thianaphthyl, isothianaphthyl, benzofuranyl, benzothienyl, isobenzofuranyl, chlomenyl, isoindolyl, indolyl, indazolinyl, isoquinolyl, quinolyl , Phthalazinyl, quinoxalinyl, quinazolinyl, synnolinyl, benzoxazinyl and the like, with pyridyl being preferred.

The "cycloalkyl" for R ² is a cycloalkyl of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The cycloalkyl radical of the "cycloalkylalkyl" for R ² is as defined for the above-defined "cycloalkyl", and the alkyl radical is as defined for the above-mentioned "lower alkyl".

Examples for a such cycloalkylalkyl include cyclopropylmethyl, 2-cyclobutylethyl, Cyclopentylmethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, Cycloheptylmethyl and the like.

The "alkenyl" for R ¹ and R ¹³ is an alkenyl having 2 to 6 carbon atoms, such as vinyl, allyl, 3-butenyl, 5-hexenyl, and the like.

The aryl radical of the "arylalkyl" for R ¹ , R ² , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹³ and R ¹⁴ is as defined for the above-mentioned "aryl", and the alkyl radical is defined as for the above-mentioned "lower alkyl". Examples of such an arylalkyl include benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2- (2-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 3- (1-naphthyl) propyl, 3 - (2-naphthyl) propyl and the like.

The heteroaryl radical of the "heteroarylalkyl" for R ¹ , R ² , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹³ and R ¹⁴ is as defined for the above-mentioned "heteroaryl", and the alkyl radical is defined as for the above-mentioned "lower alkyl". Examples of such a heteroarylalkyl include 2-pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 2- (2-pyridyl) ethyl, 2- (3-pyridyl) ethyl, 2- (4-pyridyl ) ethyl, 3- (2-pyrrolyl) propyl and the like.

The alkyl group for the alkylthio radical of the "alkylthioalkyl" for R ¹ and R ¹³ is defined as for the above-mentioned "alkyl", and the remaining alkyl group is as defined for the above-mentioned "lower alkyl". Examples of such an alkylthioalkyl include methylthiomethyl, ethylthiomethyl, N-propylthiomethyl, isopropylthiomethyl, N-butylthiomethyl, isobutylthiomethyl, sec-butylthiomethyl, tert-butylthiomethyl, and the like.

The aryl moiety of the "arylthioalkyl" for R ¹ and R ¹³ is as defined for the above-mentioned "aryl", and the alkyl moiety is as defined for the above-mentioned "lower alkyl". Examples of such arylthioalkyl include phenylthiomethyl, 1-naphthylthiomethyl, 2-naphthylthiomethyl and the like.

The heteroaryl group of "heteroarylthioalkyl" for R ¹ and R ¹³ is as defined for the above-mentioned "heteroaryl", and the alkyl group is as defined for the above-mentioned "lower alkyl". Examples of such a heteroarylthioalkyl include 2-pyrrolylthiomethyl, 2-pyridylthiomethyl, 3-pyridylthiomethyl, 4-pyridylthiomethyl, 2-thienylthiomethyl and the like.

The arylalkyl group of the "arylalkylthioalkyl" for R ¹ and R ¹³ is defined as for the above-mentioned "arylalkyl", and the remaining alkyl group is as defined for the above-mentioned "lower alkyl". Examples of a sol Arylalkylthioalkyl include benzylthiomethyl, phenethylthiomethyl and the like.

The heteroarylalkyl radical of "heteroarylalkylthioalkyl" for R ¹ and R ¹³ is as defined for the above-mentioned "heteroarylalkyl", and the remaining alkyl radical is as defined for the above-mentioned "lower alkyl". Examples of such a heteroarylalkylthioalkyl include 2-pyrrolylmethylthiomethyl, 2-pyridylmethylthiomethyl, 3-pyridylmethylthiomethyl, 4-pyridylmethylthiomethyl, 2-thienylmethylthiomethyl, and the like.

The alkyl moiety of "phthalimidoalkyl" for R ¹ and R ¹³ is as defined for the above-mentioned "lower alkyl". Examples of such a phthalimidoalkyl include phthalimidomethyl, 2-phthalimidoethyl and the like.

wobei

eine Einfachbindung ist, wenn R' und R'' jeweils Wasserstoff sind, und eine Doppelbindung ist, wenn R' und R'' in Kombination einen Ring bilden,
R''' Wasserstoff, ein Niederalkyl oder Phenyl ist,
Q' -CO-, -CH₂-, -CH(niederalkyl)-, -C(niederalkyl)-, -C(niederalkyl)₂-, -NH-, -N(niederalkyl)- oder -O- ist und
T' -O-, -NH- oder -N(niederalkyl)- ist.The A of - (CH ₂ ) 1-A for R ¹ and R ¹³ is a nitrogen-containing hetero ring bonded through a nitrogen atom and illustrated by the following groups.

in which

is a single bond when R 'and R "are each hydrogen, and is a double bond when R' and R" in combination form a ring,
R '''is hydrogen, a lower alkyl or phenyl,
Q 'is -CO-, -CH ₂ -, -CH (lower alkyl) -, -C (lower alkyl) -, -C (lower alkyl) ₂ -, -NH-, -N (lower alkyl) - or -O- and
T 'is -O-, -NH- or -N (lower alkyl) -.

Of the preferred nitrogen-containing hetero ring is represented by 2-oxo-1-pyrrolizinyl, 2,5-dioxo-1-pyrrolizinyl, 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl, 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl, 2-methyl-3,5-dioxo-1,2,4-oxadiazolidin-4-yl, 3-methyl-2,4,5-trioxo-1-imidazolidinyl, 2,5-dioxo-3-phenyl-1-imidazolidinyl and 2,6-dioxopiperidino and the like, the rings of formulas (ii) and (iii), more preferably 1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl, 3-methyl-2,5-dioxo-1-imidazolidinyl and 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl illustrated.

The abovementioned arylalkyl, heteroarylalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl, heteroarylalkylthioalkyl, phthalimidoalkyl, aryl and heteroaryl is optionally substituted by one or more substituents selected from a halogen (fluorine, chlorine, bromine, iodine), a hydroxyl group, nitro, cyano, Trifluoromethyl, a lower alkyl (provided it does not replace the alkyl radical of the arylalkyl, heteroarylalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl and phthalimidoalkyl), an alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, carboxyl, group exemplified by -COOR _a [wherein R _{a is} a lower alkyl, arylalkyl or aryl], carbamoyl, amino, lower alkylamino, di-lower alkylamino, guanidino, hydroxysulfonyloxy, arylalkyloxyalkyl and the like are selected. The terms "lower alkyl" as used herein, "Arylalkyl" and "aryl" are as mentioned above.

The "alkoxy" is a linear one or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.

Of the Alkyl residue of "alkylthio" is as for the above mentioned "lower alkyl" defined. Examples for a such alkylthio include methylthio, ethylthio, n-propylthio, isopropylthio and the same.

The "acyloxy" is a linear one or branched alkanoyloxy of 2 to 6 carbon atoms, such as Acetyloxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, hexanoyloxy and the same.

Of the Arylalkyl of "arylalkyloxyalkyl" is as for the above mentioned "arylalkyl" defined, and the remaining alkyl is as for defines the above-mentioned "lower alkyl". Examples for a such arylalkyloxyalkyl include benzyloxymethyl, phenethyloxymethyl and the same.

The "optionally substituted hetero ring" formed by R ¹⁰ and R ¹¹ together with the adjacent nitrogen atom is a 4- to 7-membered ring having one carbon atom (s) and at least one nitrogen atom and optionally as another heteroatom in the Ring has at least one kind of atom selected from nitrogen, oxygen and sulfur, wherein the carbon atom (s) constituting the ring may be substituted by oxo, and further, an aromatic ring such as a benzene ring and the like may be condensed using two adjacent carbon atoms constituting the hetero atom. Examples of such a hetero ring include azetidino, 1-pyrrolizinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino, oxothiomorpholino, dioxothiomorpholino, 2-oxo-1-quinazolinyl and the like.

When the hetero ring contains a nitrogen atom as another heteroatom in the ring, such as 1-piperazinyl, the nitrogen atom may be an arylalkyl (an above-mentioned), an arylalkyl (mentioned above), a heteroarylalkyl (mentioned above), an aryl (mentioned above), a heteroaryl (mentioned above), a group exemplified by -COOR _a (wherein R _{a is} as mentioned above) or acyl. Here, "acyl" is a group represented by -COR _a , where R _{a is} as mentioned above.

The characteristic group of the natural or non-natural α-amino acid for R ¹² is a group R in the natural or non-natural α-amino acid, which is exemplified by H ₂ N-CH (R) -COOH. Examples of the characteristic group derived from the natural α-amino acid are as follows, with the corresponding amino acids listed in parentheses: hydrogen (glycine), methyl (alanine), isopropyl (valine), isobutyl (leucine), benzyl ( Phenylalanine), p-hydroxybenzyl (tyrosine), hydroxymethyl (serine), mercaptomethyl (cysteine), 1-hydroxyethyl (threonine), 2-methylthioethyl (methionine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 2-indolylmethyl ( Tryptophan), 4-imidazolylmethyl (histidine), 4-aminobutyl (lysine), and 3-guanidinopropyl (arginine). Examples of the characteristic group derived from the non-natural α-amino acid are as follows, with the corresponding non-natural amino acids listed in parentheses: ethyl (α-amino-n-butanoic acid), n-propyl (α-amino) n-pentanoic acid), n-butyl (α-amino-n-heptanoic acid), n-heptyl (α-amino-n-nonanoic acid), cyclohexylmethyl (cyclohexylalanine), phenyl (α-aminophenylacetic acid), 2-phenylethyl (homophenylalanine), 1-naphthyl (α-amino-1-naphthylacetic acid), 2-naphthyl (α-amino-2-naphthylacetic acid), phenethyl (α-amino-3-phenylbutanoic acid), α-methylbenzyl (β-methylphenylalanine), α, α- Dimethylbenzyl (β, β-dimethylphenylalanine) and the like.

The optional (reactive) functional group present in R ¹² may be protected by a method known in peptide chemistry. For example, the amino group may be protected in the form of a tert-butoxycarbonyl, benzyloxycarbonyl or isobornyloxycarbonyl group or phthalimido group. The carboxyl group may be protected in the form of methyl, ethyl, tert-butyl, benzyl and the like. The hydroxy group may be protected in the form of tert-butyl, benzyl or tetrahydropyranyl ether or in the form of acetate. The mercapto group may be protected in the form of tert-butyl, benzyl or a similar group.

The "hydroxyl-protecting group" for X is, for example, an arylalkyl, aryl, heteroaryl, silyl (eg trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like), 2-tetrahydropyranyl and the like. The arylalkyl, aryl and heteroaryl optionally have one or more substituents, for example, a halogen (fluorine, chlorine, bromine, iodine), a hydroxyl group, nitro, cyano, trifluoromethyl, a lower alkyl (provided that it does not substitute the alkyl radical of the arylalkyl ), an alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, carboxyl, a group represented by -COOR _a [wherein R _{a is} a lower alkyl, arylalkyl or aryl], carbamoyl, amino, a lower alkylamino, di-lower alkylamino, guanidino, Hydroxysulfonyloxy, arylalkyloxyalkyl and the like are selected. The protective group of the hydroxyl group of the compound of the present invention is preferably silyl, 2-tetrahydropyranyl, benzyl and the like.

The "alkylene" for Z is a methylene chain with 1 to 5 carbon atoms, such as methylene, Ethylene, propylene, butylene or pentylene and the like.

The "phenylene" for Z is a divalent aromatic hydrocarbon group exemplified by -C ₆ H ₄ -, such as 1,2-, 1,3- or 1,4-phenylene.

The "naphthylene" for Z is a divalent aromatic hydrocarbon group exemplified by -C ₁₀ H ₆ -, such as 1,2-, 1,4-, 1,5-, 2,5- or 2,8-naphthalene and like.

The Phenylene and the naphthalene for the above mentioned Z are optionally substituted by one or more substituents, which consists of a halogen (fluorine, chlorine, bromine, iodine), a hydroxyl group, nitro, Cyano, trifluoromethyl, a lower alkyl, alkoxy, acyloxy, hydroxysulfonyl, Hydroxysulfonyloxy and the like are selected. The ones used here Terms "lower alkyl", "alkoxy" and "acyloxy" are as mentioned above.

If the sulfonic acid derivatives hydroxamic acid, which are illustrated by the formulas (I) and (II), compounds, which are illustrated by the formulas (III) and (IV), and pharmaceutically acceptable salts thereof have an asymmetric carbon, they can be present as an optically active form or as a racemate. The racemate can by means of a per se known agent in each optically active Form split. When the sulfonic acid derivative of hydroxamic acid and a pharmacologically acceptable salt thereof is an additional one Asymmetric carbon may have the compound as a diastereomer mixture or be present as a single diastereomer, which also by a per se known means can be separated.

The sulfonic acid of hydroxamic acid and a pharmacologically acceptable salt thereof have a polymorphism on and can be present as more than one tautomer, and continue to do so be present as a solvate.

Accordingly, the present Invention an above mentioned any stereoisomer, optical isomer, polymorph, tautomer, Solvate, optional mixtures thereof, and the like. An optical active form, a racemate and a diastereomer are also in the frame of the present invention included.

The pharmacologically acceptable salts of the sulfonic acid derivatives of hydroxamic acid, the are illustrated by the formulas (I) and (II), and the compounds of the formulas (III) and (IV) For example, an alkali metal salt (salt with lithium, sodium, Potassium and the like), an alkaline earth metal salt (a salt with calcium, Magnesium and the like), an aluminum salt, an ammonium salt, a salt with an organic base (triethylamine, morpholine, piperidine, Triethanolamine, trishydroxymethylaminomethane, meglumine and the like), a salt with a natural α-amino acid (alanine, Phenylalanine, histidine, lysine, arginine and the like) and the like be.

Other pharmaceutically acceptable salts may for example be an addition salt with an inorganic acid (a salt with hydrochloric acid, hydrobromic, hydroiodic, Sulfuric acid, phosphoric acid and the like), an addition salt with an organic acid (a Salt with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid and the like), a salt with an amino acid (glutamic acid, aspartic acid and the like) and the like. In addition, for crystallization a salt with oxalic acid be formed.

A preferred embodiment the sulfonic acid derivatives hydroxamic acid, which is illustrated by the formulas (I) and (II), and compounds, which are illustrated by the formulas (III) and (IV) by a free acid or a pharmacologically acceptable salt. A Crystallization is possible in both forms, and an optional derivative and an isomer thereof with high purity in a big one Amount to be produced.

Preferred embodiments of the sulfonic acid derivatives of hydroxamic acid represented by the formulas (I) and (II) and pharmacologically acceptable salts thereof are exemplified by a sulfonic acid derivative of hydroxamic acid of the formula (I) or (II) wherein R ^{1 is} phthalimidomethyl, or a pharmacologically acceptable salt thereof, a sulfonic acid derivative of hydroxamic acid of the formula (I) or (II) wherein R ^{2 is} isobutyl, or a pharmacologically acceptable salt thereof, a hydroxamic acid derivative in which R ^{3 is} hydrogen in formula (I), or a pharmacologically acceptable salt thereof, a hydroxamic acid derivative of the formula (I) wherein R ^{4 is} NHCH ₃ or NHC ₆ H ₅ , or a pharmacologically acceptable salt thereof, a sulfonic acid derivative of hydroxamic acid of formula (II) wherein R ^{12 is} benzyl, or a pharmacologically acceptable salt thereof, a sulfonic acid derivative of hydroxamic acid of formula ( II), wherein R ^{6 is} hydrogen, or a pharmacologically acceptable salt thereof, and the like.

Especially are the compounds of Examples 1, 2, 10, 11, 13, 14, 15, 17, 19, 21, and 22 preferred compounds in the examples below, these preferred embodiments lock in.

Schema 1

wobei n eine ganze Zahl von 1 bis 6 ist, R^9' wie für R⁹ definiert ist (mit Ausnahme von Wasserstoff) und R¹, R², R³, R⁴, X und Y wie oben definiert sind.The processes for producing the sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof of the present invention are listed below. A process for producing the sulfonic acid derivative of hydroxamic acid exemplified by the formula (I)

Scheme 1

wherein n is an integer from 1 to 6, R ^{9 'is} as defined for R ⁹ (except for hydrogen) and R ¹ , R ² , R ³ , R ⁴ , X and Y are as defined above.

As in the above mentioned Scheme 1 illustrates the sulfonic acid derivative of hydroxamic acid (I) or a pharmaceutically acceptable salt thereof of the present Be prepared by the carboxylic acid (VII) as a starting material by means of an amino derivative (VIII) by the method of activation of the C-terminus for the peptide synthesis [e.g. Pepuchidogousei no kiso to jikken, Izumiya et al., Maruzen Shoten, p. 91] to an intermediate compound (VIa) and over the conversion of this compound to a sulfonic acid derivative (Va) and the sulfonic acid derivative (IIIa) is converted.

The carboxylic acid (VII) as a starting material is a compound which is disclosed in a reference ( Japanese Patent Application under PCT under Kohyo No. H6-506445 disclosed, JP-A-4-352757 . JP-A-7-157470 . Japanese Patent Application under PCT under Kohyo No. H4-502008 disclosed, JP-A-6-65196 , Description of WO96 / 33968 , Description of WO94 / 21625 and the like) or produced by a conventional method based on these references.

The Amino derivative (VIII) can be exemplified by the below Process are produced.

The Details of each level are explained below.

step 1

In Stage 1 will be the carboxylic acid (VII) and the amino derivative (VIII), whereby the intermediate compound (VIa) is obtained.

The representative Procedure is listed below.

Step 1-1) Method using a mixed acid anhydride

The Intermediate compound (VIa) can be obtained by adding carboxylic acid (VII) with isobutyl chlorocarbonate in the presence of an amine base such as triethylamine, N-methylmorpholine and the like is reacted and the resulting Compound is reacted with the amino derivative (VIII). The used solvent can be an aprotic solvent such as tetrahydrofuran (THF), methylene chloride, ethyl acetate, N, N-dimethylformamide (DMF) and the like, and the reactions can be carried out at -15 ° C to room temperature.

Step 1-2) Method using an acid chloride

The carboxylic acid (VII) is reacted with oxalyl chloride or thionyl chloride, whereby to obtain an acid chloride becomes. When used solvent it is methylene chloride or a hydrocarbon solvent such as benzene, toluene and the like, and the reaction is carried out at -15 ° C to room temperature or under heating carried out. The intermediate compound (VIa) can be obtained by dissolving the obtained acid chloride with the amino derivative (VIII) in the presence of an amine base such as triethylamine, Pyridine and the like is reacted. When used solvent it is an aprotic solvent such as THF, ethyl acetate, DMF, methylene chloride, benzene, toluene and the like, and the reaction can be at -15 ° C to room temperature or under heating carried out become.

Step 1-3) Method using from DCC-HOBt (coupling method)

The Intermediate compound (VIa) can be obtained by reacting the carboxylic acid (VII) and the amino derivative (VIII) with 1,3-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt) as condensing agent in the presence of an amine base such as triethylamine or N-methylmorpholine and the like are reacted at a temperature that will not be higher is as room temperature. As a condensing agent, 1,3-diisopropylcarbodiimide (DIPCI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI · HCl) or benzotriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent) and the like can be used instead of DCC. When used solvent it is an aprotic solvent such as THF, methylene chloride, Ethyl acetate, DMF, pyridine and the like.

Step 1-4) Process using the active ester method

The carboxylic acid (VII) and a phenol derivative such as pentafluorophenol and the like or N-hydroxysuccinimide are treated with a condensing agent such as DCC and the like, thereby obtaining an active ester becomes. If necessary, an amine base is used, and the one to be used Amine base is triethylamine or N-methylmorpholine or similar. The solvent used is an aprotic solvent such as THF, DMF, methylene chloride and the like, and the reaction is carried out at a temperature not higher than Room temperature is. The intermediate compound (VIa) can be obtained by reacting the obtained active ester with an amino derivative (VIII) becomes. An amine base is used as needed, and in the case of use Amine base is triethylamine or N-methylmorpholine and the same. The solvent used is an aprotic solvent such as THF, DMF, methylene chloride and the like, and the reaction can be performed at a temperature not higher than Room temperature is.

Level 2

The sulfonic acid (Va) can be obtained by using the intermediate compound (VIa) with a haloalkanesulfonic acid or sultone in the presence of an inorganic base such as potassium carbonate or cesium carbonate and the like is implemented. When used solvent it is an aprotic solvent such as DMF, acetonitrile, Acetone and the like, and the reaction can be carried out at -15 ° C to room temperature or under heating carried out become.

level 3

In step 3, the sulfonic acid derivative (Va) is converted to the sulfonic acid derivative (IIIa). For example, when R ^{9 '} can be removed with an acid such as a tert-butyl group, the sulfonic acid derivative (Va) can be converted to the sulfonic acid derivative (IIIa) by reacting with hydrogen chloride or trifluoroacetic acid. The solvent used is an ether solvent such as 1,4-dioxane and the like or methylene chloride and the like, and the reaction can be carried out at a temperature not higher than room temperature.

Level 4

In step 4, the sulfonic acid derivative (IIIa) is capped with unprotected hydroxylamine (XONH ₂ wherein X is defined above) or with a hydroxylamine containing a silyl (trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like) Butyl, benzyl, benzyloxymethyl, p-methoxybenzyl, 2-nitrobenzyl, 2-tetrahydropyranyl group (Chem. Pharm. Bull. Jpn. 23, 167, 1975) and the like) to give the sulfonic acid derivative of Hydroxamic acid (I) is reacted. As reaction conditions, those of Step 1 can be used. When a protected hydroxylamine is used, the protecting group can be removed after the reaction under general deprotection conditions for hydroxyl groups [TW Greene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2nd Ed., (JOHN WILEY & SONS, Inc.)].

wobei n eine ganze Zahl von 1 bis 6 ist und R¹, R², R³, R⁴, R^9' und Y wie oben definiert sind.The sulfonic acid derivative (Va) may also be prepared by a method illustrated in Scheme 2 below. Scheme 2

wherein n is an integer from 1 to 6 and R ¹ , R ² , R ³ , R ⁴ , R ^{9 '} and Y are as defined above.

Level 5

In Stage 5 becomes the carboxylic acid (VII) and the amino derivative (IX), whereby the sulfonic acid derivative (Va) is obtained. This level can be done using the same procedure carried out in stage 1 become.

wobei n eine ganze Zahl von 1 bis 6 ist, X' und W gleich oder verschieden sind und wie für X definiert sind, und R¹, R², R³, R⁴, X und Y wie oben definiert sind.The sulfonic acid derivative of the hydroxamic acid (I) of the present invention can also be prepared by the method shown in the following Scheme 3. Scheme 3

wherein n is an integer of 1 to 6, X 'and W are the same or different and are as defined for X, and R ¹ , R ² , R ³ , R ⁴ , X and Y are as defined above.

Stage 6

In Stage 6 becomes the carboxylic acid (X) and the amino derivative (IX), whereby the sulfonic acid derivative (Ia) is obtained. This level can be done using the same procedure carried out in stage 1 become.

Level 7

In Step 7 becomes the sulfonic acid derivative (Ia) to the sulfonic acid derivative of hydroxamic acid (I), and it can be prepared by the same method as in step 4 independent performed by it whether W equals X or is different.

The carboxylic acid (X) can be exemplified by the scheme illustrated in Scheme 6 below Procedure performed become. The amino derivatives (VIII) and (IX) can be used, for example, with the in Scheme 5 below Process are produced.

wobei n eine ganze Zahl von 1 bis 6 ist, R¹ ein Heteroarylthioalkyl, Arylthioalkyl, Heteroarylalkylthioalkyl oder Arylalkylthioalkyl ist, R^14' wie für R¹⁴ definiert ist (mit Ausnahme von Wasserstoff) und R², R³, R⁴, R^9' und Y wie oben definiert sind.The desired substituent R ¹ can be introduced by the method illustrated in the above-mentioned Schemes 1-3 and without a specific step using the carboxylic acid (VII) or (X) having the substituent. In addition, the method illustrated in Scheme 4 below may also be used. Scheme 4

wherein n is an integer from 1 to 6, R ^{1 is} a heteroarylthioalkyl, arylthioalkyl, heteroarylalkylthioalkyl or Arylalkylthioalkyl is, R ^{14 '} as defined for R ¹⁴ (with the exception of hydrogen) and R ² , R ³ , R ⁴ , R ^9' and Y are as defined above.

Stage 8

In step 8, the carboxylic acid (XI) and the amino derivative (VIII) are reacted to obtain the intermediate compound (VIb). This step can be carried out by the same method as in Step 1. The carboxylic acid (XI) as starting material is in the literature ( JP-A-7-157470 and the like), or it is prepared by a conventional method based on these references.

Level 9

In Step 9 is the intermediate compound (VIb) and a haloalkanesulfonic acid or a sultone to obtain the sulfonic acid derivative (Vb) reacted. This step can be carried out by the same method as in Step 2.

Level 10

In Level 10 becomes the carboxylic acid (XI) and the amino derivative (IX) to obtain the sulfonic acid derivative (Vb) implemented. This stage can be done using the same procedure as in Level 1 performed become.

Stage 11

In step 11, the substituents R ^{9 '} and R ^{14' of} the sulfonic acid derivative (Vb) are removed, whereby the sulfonic acid derivative (IIIb) is obtained. For example, when R ^{9 '} and R ^14' are benzyl groups, a general catalytic hydrogenation reaction is carried out in the presence of a metal catalyst at normal pressure or under pressurization. As the metal catalyst, palladium on carbon, palladium black and the like can be used, the solvent used is an ethereal solvent such as 1,4-dioxane and the like, an ester solvent such as ethyl acetate and the like, or an alcohol solvent such as methanol, ethanol, isopropyl alcohol and the like, and the reaction may be carried out at room temperature or under heating.

Level 12

In Step 12 becomes the sulfonic acid derivative (IIIb) of a decarboxylation obtained in Step 11 subjected to it into the sulfonic acid derivative (IIIc) to convert. The solvent used is to a hydrocarbon solvent such as n-hexane, benzene, toluene and the like, and if necessary the reaction in the presence of a tertiary amine such as N-methylmorpholine, Triethylamine and the like can be carried out at room temperature or under heating.

Stage 13

In Step 13 becomes the sulfonic acid derivative (IIIb) obtained in Step 11 in the presence a secondary amine reacted with formaldehyde, thereby forming the sulfonic acid derivative (IIId) is implemented. As a secondary amine, piperidine, Diethylamine, morpholine and the like used, and the reaction can be in an alcohol solvent such as methanol, ethanol and the like or an amide solvent such as DMF and the like at room temperature or under heating.

Level 14

In step 14, the sulfonic acid derivative (IIId) obtained in step 13 is reacted with an arylthiol, heteroaryithiol, alkylthiol, heteroarylalkylthiol or arylalkylthiol nucleophile to give the sulfonic acid derivative (IIIa) wherein the substituent R ^{1 is} arylthioalkyl, heteroarylthioalkyl, alkylthioalkyl, heteroarylalkylthioalkyl or arylalkylthioalkyl. This reaction can be carried out without a solvent or in a halogenated hydrocarbon solvent such as methylene chloride and the like, an alcohol solvent such as methanol and the like, or an amide solvent such as DMF and the like at room temperature or under heating.

wobei n eine ganze Zahl von 1 bis 6 ist, A' eine Amino-Schutzgruppe wie tert-Butoxycarbonyl, Benzyloxycarbonyl und dergleichen ist, L ein Alkoxy, eine Hydroxylgruppe, ein Halogenatom wie Chlor, Brom, Iod und dergleichen ist, das davon abgeleitet werden kann, oder ein Sulfonsäureester wie Methansul fonyloxy, p-Toluolsulfonyloxy, Trifluormethansulfonyloxy und dergleichen ist und R³, R⁴ und Y wie oben definiert sind.The amino derivatives (VIII) and (IX), which are the starting compounds in Schemes 1-4, can be prepared by the method illustrated in Scheme 5 below. Scheme 5

wherein n is an integer of 1 to 6, A 'is an amino-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl and the like, L is an alkoxy, a hydroxyl group, a halogen atom such as chlorine, bromine, iodine and the like derived therefrom or a sulfonic acid ester such as methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like, and R ³ , R ⁴ and Y are as defined above.

Level 15

In Step 15 becomes compound (XIIa) and various amines or alcohols to obtain compound (XIIb). This level can by means of same procedure as in step 1.

Stage 16

In Step 16 removes the amino-protecting group from compound (XIIb) whereby the amino derivative (VIII) is obtained.

When the protecting group A 'is a tert-butoxycarbonyl group, it may be under acidic conditions are removed using trifluoroacetic acid, dioxane containing hydrogen chloride, hydrogen chloride-containing methanol, acetic acid containing hydrochloric acid, and the like. The inert solvent to be used is preferably a halogenated hydrocarbon solvent such as methylene chloride, chloroform and the like, an ethereal solvent such as diethyl ether, THF, dioxane and the like, an alcohol solvent such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol and the like or an organic acid such as acetic acid and the like.

The Reaction temperature is generally 0-100 ° C, preferably 0-50 ° C. The reaction time is generally 15 minutes-12 hours, preferably 15 minutes-4 hours.

If the protective group A 'a Benzyloxycarbonylgruppe is a method for removal by a Treatment with an acid or a method of removal by means of a catalytic reduction prefers.

The Acid, the for It is preferable to use the method in which an acid is used Trifluoromethanesulfonic acid. For the solvent to be used it is preferably methylene chloride. The reaction temperature or the reaction time are preferably 0-50 ° C or 5min-6h.

at the catalyst for the method based on a catalytic reduction is preferably palladium on carbon or palladium black. For the solvent to be used it is preferably an alcohol solvent such as methanol, ethanol, n-propyl alcohol, Isopropyl alcohol and the like, an ethereal solvent such as diethyl ether, Tetrahydrofuran, 1,4-dioxane and the like, an ester solvent such as ethyl acetate and the like. The hydrogen pressure at this Procedure is generally 1-10 atm, and the reaction temperature or reaction time are preferably 0-100 ° C. or 5min-24h.

Level 17

In Step 17 is the compound (XIIb) and the haloalkanesulfonic acid or reacted the sultone to obtain compound (XIIc). This level can be carried out by the same method as in step 2.

Level 18

In Step 18, the amino-protecting group of compound (XIIc) is removed, whereby the amino derivative (IX) is obtained, and it can with the same Procedure as in step 16.

Level 19

In Step 19 is alkylating compound (XIIb) to give a compound (XIId: L = leaving group) with a leaving group at the end by means of in a single step or in stages, what about the same Method as in method 1) or 2) can be performed below listed are.

Step 19-1) One Step Synthetic Procedure

The Compound (XIIb) is reacted with an alkylating agent, thereby it is converted to a compound (XIId: L = halogen), and it can be carried out by the same method as in step 2. When Alkylating agent may be an alkyl dihalide having a desired Carbon chain such as dibromomethane, 1,2-dibromoethane, 1-chloro-3-bromopropane, 1-chloro-4-bromobutane, 1-chloro-5-bromopentane and the like become.

Step 19-2) Synthesis Procedure in Steps

• i) Stufe zur Umwandlung von Verbindung (XIIb) in Verbindung (XIId: L = Alkoxy) durch die Umsetzung mit einem einfach geschützten Diol mit einer gewünschten Länge der Kohlenstoffkette mittels der Mitsunobu-Reaktion [J. Med. Chem., 1994, 37, 674] zur Umwandlung davon. Als einfach geschütztes Diol können 2-Benzyloxyethanol, 2-t-Butyldimethylsiloxyethanol, 3-Benzyloxypropanol, 4-Benzyloxybutanol, 5-Benzyloxypentanol und dergleichen verwendet werden. Als Aktivierungsreagens sind Triphenylphosphin und Diethylazodicarboxylat (DEAD) bevorzugt. Beim verwendeten Lösungsmittel handelt es sich um ein aprotisches Lösungsmittel wie DMF, Acetonitril, THF, Dioxan, Methylenchlorid, Chloroform und dergleichen. Diese Stufe kann bei –15 °C bis Raumtemperatur oder unter Erwärmen durchgeführt werden.
• ii) Stufe zur Umwandlung von Verbindung (XIId: L = Alkoxy) in Verbindung (XIId: L = Hydroxylgruppe) durch Schutzgruppenentfernung, die auf dieselbe Weise wie in Stufe 4 durchgeführt werden kann.
• iii) Stufe zur Umwandlung der Hydroxylgruppe von Verbindung (XIId: L = Hydroxylgruppe) in Verbindung (XIId: L = Abgangsgruppe) mit einer Abgangsgruppe wie einem Halogen, einem Sulfonsäureester und dergleichen. Wenn L ein Halogen ist, kann diese Stufe durchgeführt werden, indem die Verbindung (XIId: L = Hydroxylgruppe) mit Kohlenstofftetrachlorid oder Kohlenstofftetrabromid in Gegenwart von Triphenylphosphin umgesetzt wird. Als Lösungsmittel kann ein aprotisches Lösungsmittel wie Acetonitril, THF, Dioxan, Methylenchlorid, Chloroform und dergleichen verwendet werden. Die Reaktionstemperatur dieser Stufe beträgt vorzugsweise –15 °C bis Raumtemperatur, oder sie findet unter Erwärmen statt. Wenn L ein Sulfonsäureester ist, kann diese Stufe erfolgen, indem die Verbindung (XIId: L = Hydroxylgruppe) mit einem gewünschten Sulfonylierungsmittel in Gegenwart einer Aminbase durchgeführt wird. Als Sulfonylierungsmittel sind Methansulfonsäureanhydrid, Trifluormethansulfonsäureanhydrid und p-Toluolsulfonylchlorid bevorzugt, und als Aminbase sind Triethylamin, Pyridin, 2,6-Lutidin, 2,4,6-Collidin, Diisopropylethylamin und dergleichen bevorzugt. Als Lösungsmittel kann ein aprotisches Lösungsmittel wie Acetonitril, THF, Dioxan, Toluol, Methylenchlorid, Chloroform und dergleichen verwendet werden. Die Reaktionstemperatur dieser Stufe beträgt vorzugsweise –15 °C bis Raumtemperatur.

This method consists of the following three stages i) to iii).

• i) step of converting compound (XIIb) into compound (XIId: L = alkoxy) by reaction with a monoprotected diol having a desired length of carbon chain by the Mitsunobu reaction [J. Med. Chem., 1994, 37, 674] for the conversion thereof. As the monoprotected diol, 2-benzyloxyethanol, 2-t-butyldimethylsiloxyethanol, 3-benzyloxypropanol, 4-benzyloxybutanol, 5-benzyloxypentanol and the like can be used. Activation reagents are triphenylphosphine and diet hylazodicarboxylate (DEAD) is preferred. The solvent used is an aprotic solvent such as DMF, acetonitrile, THF, dioxane, methylene chloride, chloroform and the like. This step can be carried out at -15 ° C to room temperature or with heating.
• ii) step for converting compound (XIId: L = alkoxy) in compound (XIId: L = hydroxyl group) by deprotection, which can be carried out in the same manner as in Step 4.
• iii) Step for converting the hydroxyl group of compound (XIId: L = hydroxyl group) into compound (XIId: L = leaving group) having a leaving group such as a halogen, a sulfonic acid ester and the like. When L is a halogen, this step can be carried out by reacting the compound (XIId: L = hydroxyl group) with carbon tetrachloride or carbon tetrabromide in the presence of triphenylphosphine. As the solvent, an aprotic solvent such as acetonitrile, THF, dioxane, methylene chloride, chloroform and the like can be used. The reaction temperature of this step is preferably -15 ° C to room temperature, or it takes place under heating. When L is a sulfonic acid ester, this step can be carried out by carrying out the compound (XIId: L = hydroxyl group) with a desired sulfonylating agent in the presence of an amine base. As sulfonylating agents, methanesulfonic anhydride, trifluoromethanesulfonic anhydride and p-toluenesulfonyl chloride are preferable, and as the amine base, triethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, diisopropylethylamine and the like are preferable. As the solvent, an aprotic solvent such as acetonitrile, THF, dioxane, toluene, methylene chloride, chloroform and the like can be used. The reaction temperature of this step is preferably -15 ° C to room temperature.

Level 20

In Step 20 becomes the compound obtained in Step 19 (XIId: L = leaving group) converted into compound (XIIc). This stage may be after in the Reference [F. Cortes, Organic Synthesis, II, 564 (1943)] Procedure performed become. As hydroxysulfonylating agents are sodium sulfite, sodium hydrogen sulfite and the like are preferable. As a solvent can Water or a hydrous alcohol can be used. The reaction temperature this level is preferably room temperature, or it is carried out with heating.

wobei X' und W wie für X, R^9' und R^14' definiert sind und gleich oder in Kombination eine cyclische Struktur wie eine Methylengruppe (-CH₂-) oder Dimethylmethylen [-C(CH₃)₂-] einnehmen können, R^15' wie für R^9' und R^14' definiert ist (mit der Maßgabe, dass R^15' aus Gruppen ausgewählt ist, die von R^9' und R^{14 '} verschieden sind), und R¹, R², R^9', R^14' und X wie oben definiert sind.The carboxylic acid (X), which is a starting compound in Scheme 3, can be prepared by the method illustrated in Scheme 6 below. Scheme 6

where X 'and W are as defined for X, R ^9' and R ^{14 '} and can assume a cyclic structure, such as a methylene group (-CH ₂ -) or dimethylmethylene [-C (CH ₃ ) ₂ -], in the same or in combination, R ^{15 'is} defined (with the proviso that R ^{15' 'as} defined for R ^9' and R ¹⁴ is selected from groups which are different from R ^{9 'and} R ^14'), and R ^1, R ^2, R ^{9 '} , R ^14' and X are as defined above.

Stage 21

In step 21, compound (XIa) is converted to compound (XIb) by deprotection. For example, when R ^{15 '} is a benzyl group and R ^9' and R ^{14 'are} t-butyl groups, a method similar to that of Step 3 may be used, and in the opposite case (R ^15' : t-butyl group, R ^{9 '} and R ^14' : benzyl), the same procedure as in step 11 can be used. The compound (XIa) as the starting material is a compound which is disclosed in U.S. Pat JP-A-7-157470 or a compound prepared by a conventional method based on this reference.

Level 22

In Step 22 becomes Compound (XIb) by a decarboxylation reaction with a procedure be carried out may be similar to that of step 12 in compound (VIIa) transformed.

Stage 23

In step 23, compound (VIIa) is reacted with an N, O-disubstituted hydroxylamine [X'ON (W) H] to convert it to compound (Xa), which conversion can be carried out by a method similar to that used in step 1 is similar. The N, O-disubstituted hydroxylamine [X'ON (W) H] can be prepared by a conventional method using an O-protected hydroxylamine [X'ONH ₂ ], which is commercially available, or it can be prepared by the Methods described in a reference (Chem. Pham. Bull. Jpn. 1975, 23, 167).

Level 24

In Step 24 becomes compound (Xa) by deprotection in the carboxylic acid (X), wherein the protecting group is replaced by that in a reference [T. W. Greene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2. Edition (JOHN WILEY & SONS, Inc.)] can be removed.

The Compound (XIIa), which is the starting compound in Scheme 5 can be prepared by the following procedure.

veranschaulicht wird, mit einer Amino-Schutzgruppe wie einer tert-Butoxycarbonylgruppe, einer Benzyloxycarbonylgruppe und dergleichen [z.B. Pepuchidogousei no kiso to jikken, Izumiya et al., Maruzen Shoten, S. 16] geschützt wird.The compound (XIIa) can be prepared by reacting an amino group of an amino acid represented by the formula:

is protected with an amino-protecting group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group and the like [eg, Pepuchidogousei no kiso jikken, Izumiya et al., Maruzen Shoten, p. 16].

Schema 7

wobei R^6' und R^6' wie für R⁶ definiert sind (mit der Maßgabe, dass R^6' nicht Wasserstoff ist), X' wie für X definiert ist und R¹, R², R⁶, R¹², X und Z wie oben definiert sind.A process for producing a sulfonic acid derivative of hydroxamic acid exemplified by the formula (II)

Scheme 7

wherein R ^{6 '} and R ^{6' are} as defined for R ⁶ (provided that R ^{6 'is} not hydrogen), X' is as defined for X and R ¹ , R ² , R ⁶ , R ¹² , X and Z are as defined above.

The sulfonic acid (II) hydroxamic acid and a pharmacologically acceptable salt thereof of the present Invention can be synthesized by the method illustrated in Scheme 7. First, be the carboxylic acid (VII) and the amino derivative (XVIII) with the C-terminal activation method of Peptide synthesis [e.g. Pepuchidogousei no kiso to jikken, Izumiya et al., Maruzen Shoten, p. 91], whereby the intermediate compound (XVII), which is then converted into the succinic acid derivative (XVI) becomes. Then it becomes the O-protected hydroxamic acid derivative (XV) and after conversion to the intermediate (XIV) and then into the sulfonic acid derivative the O-protected hydroxamic acid (XIII) becomes the acid (XIII) deprotected.

The carboxylic acid (VII) as starting material is as mentioned above, and the amino derivative (XVIII) can be prepared, for example, by the method described in US Pat to explain the following Scheme 11 is.

The Details of each step are explained below.

Level 25

In Level 25 becomes the carboxylic acid (VII) and the amino derivative (XVIII) to obtain the intermediate compound (XVII), the reaction being carried out by a process may be similar to that of step 1.

Level 26

In Step 26 becomes the intermediate compound (XVII) in a succinic acid derivative (XVI), the reaction being carried out by a process which is similar to that of level 3.

Level 27

In step 27, a succinic acid derivative (XVI) is converted to an O-protected hydroxamic acid derivative (XV) The reaction may be carried out by a method similar to that of Step 4.

Stage 28

In step 28, the O-protected hydroxamic acid derivative (XV) is converted by deprotection to the intermediate (XIV). When R ^{6 'is} a benzyl group in this step, a method of deprotection by catalytic reduction is preferred. The catalyst for the process by a catalytic reduction is preferably palladium on carbon or palladium black. The solvent is preferably an alcohol solvent such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol and the like, an ethereal solvent such as diethyl ether, THF, 1,4-dioxane and the like, or an ester solvent such as ethyl acetate and the like. In this reaction, the hydrogen pressure is generally 1-10 atm, and the reaction temperature and the reaction time are preferably 0-100 ° C and 5 min-24 h.

Level 29

In step 29, the intermediate compound (XIV) is reacted with an aminoalkanesulfonic acid derivative: R ^{6 "} -NH-Z-SO ₃ H (wherein R ^6" and Z are as defined above) to give a sulfonic acid derivative of the O-protected hydroxamic acid (XIII) is obtained. This step can be carried out by the same method as in Step 1.

Level 30

In Step 30 becomes the sulfonic acid derivative the O-protected hydroxamic acid (XIII) into the sulfonic acid derivative (II) hydroxamic acid transformed. The protective group of the sulfonic acid derivative of O-protected hydroxamic acid (XIII) may under general conditions to remove a hydroxyl protecting group as in Level 4 are removed.

wobei R¹, R², R¹², R^6'', R^{9 '}, X' und Z wie oben definiert sind.The sulfonic acid derivative of the O-protected hydroxamic acid (XIII) can also be prepared by the method illustrated in Scheme 8 below. Scheme 8

wherein R ¹ , R ² , R ¹² , R ^{6 "} , R ^{9 '} , X' and Z are as defined above.

Stage 31

In Stage 31 becomes the carboxylic acid (VII) and the amino derivative (XIX) to obtain the intermediate compound (XXa) implemented. This stage can be done using the same procedure as in Level 1 performed become.

Stage 32

In Step 32 becomes an intermediate compound (XXa) in the succinic acid derivative (XXIa) converted. This level can be done using the same procedure carried out in stage 3 become.

Stage 33

In Step 33 becomes a succinic acid derivative (XXIa) in a sulfonic acid derivative an O-protected hydroxamic acid (XIII) converted. This level can be done using the same procedure carried out in stage 4 become.

wobei W wie für X' definiert ist und gleich oder verschieden sein kann und R¹, R², R¹², R^6'', X' und Z wie oben definiert sind.The sulfonic acid derivative of the O-protected hydroxamic acid (XIII) can also be carried out by a process as shown in Scheme 9 below, or a process similar to that illustrated in Scheme 3 for a sulfonic acid derivative (I) of hydroxamic acid. Scheme 9

wherein W is as defined for X 'and may be the same or different and R ¹ , R ² , R ¹² , R ^{6 "} , X' and Z are as defined above.

Level 34

In Stage 34 becomes the carboxylic acid (X) and the amino derivative (XIX) to obtain the sulfonic acid derivative (XIIIa) implemented. This level can be done using the same procedure carried out in stage 1 become.

Level 35

In Step 35 becomes the sulfonic acid derivative (XIIIa) into a sulfonic acid derivative (XIII) of hydroxamic acid transformed. This stage can be done with the same procedure as in stage 7 performed become.

The carboxylic acid (X) can after the above mentioned Scheme 6, and the amino derivatives (XVIII) and (XIX) can For example, be prepared with the method explained in Scheme 11 below.

wobei R¹ ein Heteroarylthioalkyl, Arylthioalkyl, Heteroarylalkylthioalkyl, Alkylthioalkyl oder Arylalkylthioalkyl ist, R^14' wie für R¹⁴ definiert ist (mit Ausnahme von Wasserstoff), und R², R¹², R^6'', R^{9 '} und Z wie oben definiert sind.The desired substituent R ¹ can be introduced without a specific step but by the methods recited in the above-mentioned Schemes 7 and 8 using the carboxylic acid (VII) having the substituent. Besides, it can also be produced by using the carboxylic acid (XI) and the amino derivative (XIX) by the same method as in Scheme 4 for the sulfonic acid derivative (I) of hydroxamic acid. Scheme 10

wherein R ^{1 is} a heteroarylthioalkyl, arylthioalkyl, heteroarylalkylthioalkyl, alkylthioalkyl or arylalkylthioalkyl, R ^{14 'is} as defined for R ¹⁴ (with the exception of hydrogen), and R ² , R ¹² , R ^{6 "} , R ^{9 '} and Z are as above are defined.

Level 36

In step 36, the carboxylic acid (XI) and the amino derivative (XIX) are reacted to give the intermediate (XXIIa). This step can be carried out by the same method as in Step 1. The carboxylic acid (XI), which is said to be the starting material, is a compound disclosed in references ( JP-A-7-157470 and the like), or a compound prepared by a conventional method based on the references.

Level 37

In step 37, the substituents R ^{9 '} and R ^{14' of} the intermediate (XXIIa) are removed to obtain the succinic acid derivative (XXIIb). This step can be carried out by the same method as in Step 11.

Stage 38

In Step 38 becomes the succinic acid derivative obtained in step 37 (XXIIb) by a decarboxylation in the succinic acid derivative (XXIIc) converted. This level can be done using the same procedure in stage 12.

Level 39

In Step 39 becomes the succinic acid derivative obtained in Step 37 (XXIIb) by a reaction with formaldehyde in the presence of a secondary amine into the succinic acid derivative (XXIId) converted. This level can be done using the same procedure in stage 13.

Level 40

In step 40, the succinic acid derivative (XXIId) obtained in step 39 is reacted with an arylthiol, heteroaryithiol, alkylthiol, heteroarylalkylthiol or arylalkylthiol nucleophile to give the succinic acid derivative (XXIa) wherein the substituent R ^{1 is} an arylthioalkyl, heteroarylthioalkyl, alkylthioalkyl, heteroarylalkylthioalkyl or arylalkylthioalkyl. This step can be carried out by the same method as in Step 14.

wobei A' eine Amino-Schutzgruppe wie tert-Butoxycarbonyl, Benzyloxycarbonyl und dergleichen ist und R¹², R^6', R^6'' und Z wie oben definiert sind.The amino derivatives (XVIII) and (XIX), which are the starting compounds in Schemes 7-10, can be prepared by the method illustrated in Scheme 11 below. Scheme 11

wherein A 'is an amino-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl and the like and R ¹² , R ^6' , R ^{6 "} and Z are as defined above.

Stage 41

In Step 41 is the compound (XXIIIa) and an alcohol derivative such as Benzyl alcohol and the like to obtain compound (XXIIIb) implemented. This stage can be done with the same procedure as in stage 1 performed become.

Level 42

In Step 42, the amino-protecting group of compound (XXIIIb) is removed, whereby the amino derivative (XVIII) is obtained, the removal with the same procedure as in step 16.

Stage 43

In step 43, the compound (XXIIIa) and the aminoalkanesulfonic acid derivative: R ^{6 "} -NH-Z-SO ₃ H (wherein R ^{6 "} and Z are as defined above) are reacted to obtain compound (XXIIIc). This step can be carried out by the same method as in step 29.

Level 44

In Step 44, the amino-protecting group of compound (XXIIIc) is removed, whereby the amino derivative (XIX) is obtained, the removal with the same procedure as in step 16.

The Compound (XXIIIa), which is the starting compound in Scheme 10, can be prepared by the following method.

mit Aminoschutzgruppe wie einer tert-Butoxycarbonylgruppe, Benzyloxycarbonylgruppe und dergleichen [z.B. Ppeuchidogousei no kiso to jikken, Izumiy et al, Maruzen Shoten, S. 16] geschützt wird.The compound (XXIIIa) can be prepared by reacting an amino group of an amino acid of the formula

with amino protecting group such as a tert-butoxycarbonyl group, benzyloxycarbonyl group and the like [eg Ppeuchidogousei no kiso to jikken, Izumiy et al., Maruzen Shoten, p. 16].

Conversion and the like between various substituents including R ³ are possible not only at a certain stage but at any stage as long as it is under the conditions which do not affect other functional groups existing in the chemical structural formula.

The so synthesized sulfonic acid derivative of hydroxamic acid of the present invention can be isolated in an optional purity be prepared by known separation and cleaning agents such as a concentration, extraction, Chromatography, Precipitation, Recrystallization and the like are suitably applied.

Furthermore can a pharmacologically acceptable salt and solvate of the sulfonic acid derivative of hydroxamic acid be prepared by a known method. Furthermore can various isomers and the like of the sulfonic acid derivative of hydroxamic acid be prepared by a known method.

The sulfonic acid of hydroxamic acid and a pharmacologically acceptable salt of the present invention have a superior LPS inhibitory effect on mammals (e.g., the human, dog, cat, and the like) and are few toxic.

Therefore are the sulfonic acid derivative of hydroxamic acid and a pharmacologically acceptable salt thereof of the present Invention as LPS inhibitor useful and for prophylaxis or treatment of diseases such as sepsis, MOF, chronic rheumatoid arthritis, Crohn's disease, cachexia, myasthenia gravis, systemic lupus erythematodus, Asthma, type 1 diabetes, psoriasis, other autoimmune diseases, inflammatory diseases and the like.

If the sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof of the present Invention is used as a pharmaceutical, a pharmacological acceptable vehicle and the like, and they may be administered orally or parenterally pharmaceutical composition in the form of a granule, a tablet, a capsule, an injection, an ointment, eye drops, nose drops, a cream, an aerosol and the like. Especially are the sulfonic acid derivative of hydroxamic acid and a pharmacologically acceptable salt thereof with respect to Superior to water solubility and for the preparation of a water-soluble pharmaceutical composition like an injection, eye drops, nose drops, a remedy for Drops and the like are preferred.

The mentioned above preparation contains an effective amount of the sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof.

The dose of the sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof varies depending on the route of administration, the condition, the body weight or the age of patients and the like, and may be appropriately determined depending on the patient. For oral administration to an adult, it is generally 0.01-1000 mg / kg body weight / day, preferably 0.05-250 mg / kg body weight / day, preferably once a day or more doses per day.

The The present invention will now be described with reference to examples. not as limiting may be understood in detail explained.

¹ H NMR was measured at 270 MHz or 300 MHz. The chemical shift of ¹ H-NMR is expressed as relative delta (δ) values in parts per million (ppm) using tetramethylsilane as the internal standard. For the coupling constant, an apparent multiplicity in Hertz (Hz) is given, where s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), br s ( broad singlet) and the like. Example 1 (1) 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

(1) 1,2-Dibenzyl-1-tert-butyl-4-methyl-1,1,2- (R) -pentanetricarboxylate

The synthesis was carried out using (D) -leucine as the starting material and in the same manner as in JP-A-4-352757 described method performed.
¹ H-NMR _(CDCl3) δ 7:45 to 7:20 (m, 10H), 5.25-4.93 (m, 4H), 3.68 and 3.65 (d, J = 9.8 Hz, 1H), 3:25 to 3:08 (m, 2H), 1.68-1.38 (m, 2H), 1.34 and 1.33 (s, 9H), 1.35-1.05 (m, 1H), 0.90, 0.84, 0.83 and 0.78 (d, J = 6.4 Hz, 6H).

(2) 4-tert-butoxy-2 (R) -isobutyl-3 (R or S) -phthalimidomethylbernsteinsäure

Using the title compound of Example 1 (1) and N-bromomethylphthalimide and in the same manner as in JP-A-4-352757 described method, a crude product was obtained. The purification was carried out by the following procedure. The crude product (607 g, about 1.32 mol) was dissolved in diisopropyl ether (6 L), cyclohexylamine (151 mL, 1.32 mol) was added under ice-cooling, and the mixture was stirred for 1.5 h. The precipitate was isolated by filtration, washed (diisopropyl ether) and dried in air. The resulting solid was suspended in ethyl acetate (0.4 L) and washed successively with 2N aqueous sulfuric acid solution (1.32 L), water (2 L x 2) and saturated brine (2 L). The organic layer was dried over anhydrous magnesium sulfate and filtered after treatment with activated carbon (25 g / 70 ° C / 30 min). The filtrate was concentrated under reduced pressure to give the title compound (467.6 g, 91%, 68% de) as an oil.
¹ H-NMR _(CDCl3) δ 7.90-7.65 (m, 4H), 4.13 (dd, J = 14.0, 9.1 Hz, 1H), 3.77 (dd, J = 14.0, 5.4 Hz, 1H), 3:25 to 3:10 ( m, 1H), 2.88-2.75 (m, 1H), 1.85-1.60 (m, 2H), 1.35 (s, 9H), 1.35-1.20 (m, 1H), 0.93 (d, J = 6.5 Hz, 6H) ,

(3) N ^α - (tert-butoxycarbonyl) -L-tyrosine N-methylamide

To a solution of N- (tert-butoxycarbonyl) -L-tyrosine (300 g, 1.07 mol) in DMF (2 L) was sequentially added methylamine hydrochloride (86.4 g, 1.28 mol), 1-hydroxybenzotriazole monohydrate (163 g, 1.07 mol, hereinafter abbreviated as HOBt · H ₂ O), N-methylmorpholine (258 ml, 2.35 mol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (245 g, 1.28 mol , hereinafter abbreviated as WSCl · HCl) under ice-cooling (internal temperature 10 ° C). The reaction mixture was stirred for 70 hours while the temperature was gradually raised to room temperature. The reaction mixture was poured into ice-water (10 L) and the precipitate was isolated by filtration and washed with water and ether. The resulting precipitate was recrystallized from ethyl acetate (7 L) to give the title compound (265 g, 84%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ 9.14 (s, 1H), 7.76 (d, J = 4.5 Hz, 1H), 7.00 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.4 Hz , 2H), 6.63 (d, J = 8.1 Hz, 2H), 4.08-3.85 (m, 1H), 2.79 (dd, J = 13.7, 4.7 Hz, 1H), 2.70-2.55 (m, 1H), 2.56 ( d, J = 4.2 Hz, 3H), 1.37 (s, 9H).

(4) L-tyrosine N-methylamide hydrochloride

The title compound (160 g, 0.54 mol) of Example 1 (3) was dissolved in a mixed solvent of chloroform (800 ml) and methanol (400 ml), and anisole (295 ml, 2.72 mol) and a 4N Hydrochloric acid-dioxane solution (800 ml) was added under ice-cooling (internal temperature 7 ° C). The mixture was stirred for 2 hours at this temperature and for 2 hours at room temperature. Diisopropyl ether (2 L) was added to the reaction solution and the precipitate was isolated by filtration, washed with diisopropyl ether and dried to give the title compound (125 g, quantitative determination) as a white solid.
[α] _D ²⁴ = + 75.2 (c = 1.0, H ₂ O).
¹ H-NMR (DMSO-d ₆ ) δ 9.80-9.05 (br, 1H), 8.41 (q, J = 4.8 Hz, 1H), 8.40-8.00 (br, 3H), 7.00 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 3.90-3.75 (m, 1H), 2.93 (dd, J = 13.8, 6.9 Hz, 1H), 2.87 (dd, J = 13.8, 7.2 Hz, 1H ), 2.58 (d, J = 4.8 Hz, 3H).

(5) tert -butyl-3 (R) - {2- (4-hydroxyphenyl) -1 (S) - (methylcarbamoyl) ethylcarbamoyl] -5-methyl-2 (R. or S) -phthalimidomethylhexanoate

To a solution of the title compound (200 g, 0.51 mol) of Example 1 (2) and the title compound (118 g, 0.51 mol) of Example 1 (4) in DMF (1 L) was added HOBt · H ₂ O (78.6 g, 0.51 mol), N-methylmorpholine (113 mL, 1.03 mol) and WSCI · HCl (118 g, 0.62 mol) were added under ice-cooling (internal temperature 10 ° C). The reaction mixture was stirred for 16 hours, gradually raising the temperature to room temperature. The reaction solution was poured into ice-water (5 L), and the precipitate was isolated by filtration. The resulting precipitate was dissolved in ethyl acetate (3 L), washed successively with 0.5 N hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine (each 1 L), dried (anhydrous magnesium sulfate) and concentrated under reduced pressure , The resulting residue was recrystallized from ethyl acetate (1.9 L) -diisopropyl ether (1 L) to give the title compound (201 g, 69%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ 8.75 (s, 1H), 8.37 (d, J = 9.0 Hz, 1H), 7.95-7.70 (m, 5H), 7.04 (d, J = 8.4 Hz, 2H) , 6.46 (d, J = 8.4 Hz, 2H), 4.65-4.50 (m, 1H), 3.40 (dd, J = 13.7, 11.7 Hz, 1H), 2.87 (dd, J = 13.7, 4.5 Hz, 1H), 2.70-2.50 (m, 3H), 2.59 (d, J = 4.8 Hz, 3H), 2.27 (dd, J = 13.7, 5.1 Hz, 1H), 1.58-1.44 (m, 1H), 1.42-1.25 (m, 1H), 1.09 (s, 9H), 0.90-0.70 (m, 1H), 0.84 (d, J = 6.6Hz, 3H), 0.76 (d, J = 6.6Hz, 3H).

(6) tert -butyl-5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanoatecazium salt

To a solution of the title compound (91.2 g, 161 mmol) of Example 1 (5) in DMF (500 mL) were added 1,3-propanesultone (21.7 g, 177 mmol) and cesium carbonate (57.8 g, 177 mmol) at room temperature, and the mixture was stirred for 45 hours. Diisopropyl ether (2 L) was added to the reaction solution and the precipitate was isolated by filtration, washed with ethyl acetate and dried to give the title compound (159 g, quantitative determination) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 8.43 (d, J = 9.0 Hz, 1H), 8.00-7.80 (m, 5H), 7.17 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 4.70-4.55 (m, 1H), 3.70-3.10 (m, 3H), 3.00-2.85 (m, 1H), 2.75-2.35 (m, 3H), 2.61 (d, J = 4.5 Hz , 3H), 2.16 (t, J = 7.4 Hz, 2H), 1.98 (dd, J = 13.5, 4.5 Hz, 1H), 1.60-1.42 (m, 1H), 1.40-1.20 (m, 3H), 1.09 ( s, 9H), 0.90-0.70 (m, 1H), 0.85 (d, J = 6.5 Hz, 3H), 0.76 (d, J = 6.5 Hz, 3H).

(7) 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanoic acid

The title compound (159 g, 161 mmol) of Example 1 (6) was suspended in methylene chloride (500 ml), and trifluoroacetic acid (500 ml) was added under ice-cooling (internal temperature 5 ° C). The mixture was stirred at room temperature for 4.5 hours. Diisopropyl ether (2 L) was added to the reaction solution, and the precipitate was isolated by filtration. The resulting precipitate was recrystallized from 1.2 N hydrochloric acid (3.5 L) to give the title compound (77.7 g, 76%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ 8.37 (d, J = 8.8 Hz, 1H), 7.95-7.80 (m, 5H), 7.17 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.6 Hz, 2H), 4.75-4.57 (m, 1H), 3.55-3.35 (m, 2H), 3.24 (dd, J = 13.5, 11.1 Hz, 1H), 2.93 (dd, J = 13.6, 3.9 Hz, 1H ), 2.72-2.55 (m, 1H), 2.62 (d, J = 4.6 Hz, 3H), 2.55-2.42 (m, 2H), 2.22 (t, J = 7.4 Hz, 2H), 2.07 (dd, J = 13.5, 3.7Hz, 1H), 1.60-1.20 (m, 4H), 0.95-0.75 (m, 1H), 0.84 (d, J = 6.5Hz, 3H), 0.76 (d, J = 6.5Hz, 3H).

(8) 2-Tetrahydropyranyl-5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamate sodium salt

To a solution of the title compound (13.80 g, 21.8 mmol) of Example 1 (7) in DMF (50 mL) was sequentially added N-methylmorpholine (4.8 mL, 43.7 mmol), O-2-tetrahydropyranylhydroxylamine (3.07 g, 26.2 mmol), HOBt · H ₂ O (3.35 g, 21.8 mmol) and WSCl · HCl (5.03 g, 26.2 mmol) under ice-cooling (internal temperature 10 ° C ). The reaction mixture was stirred for 18 hours while the temperature was gradually raised to room temperature. The reaction solution was poured into an aqueous solution (500 ml) of sodium dihydrogen phosphate dihydrate (17.00 g, 109 mmol) saturated with sodium chloride and extracted (500 ml × 3) with a solvent mixture of THF-methanol (10/1) , Butanol was added to the extract solution and the mixture was concentrated under reduced pressure. Diisopropyl ether (1 L) was added to the residue and the precipitate was isolated by filtration and dried to give the title compound (30.20 g, quantitative determination) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 10.89 and 10.85 (br s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.00-7.88 (m, 1H), 7.88-7.75 (m, 4H) , 7.19 (d, J = 8.7 Hz, 2H), 6.53 (d, J = 8.7 Hz, 2H), 4.70-4.55 (m, 1H), 4.52 and 4.37 (br s, 1H), 3.75-3.00 (m, 5H), 2.93 (dd, J = 13.7, 4.1 Hz, 1H), 2.78-2.58 (m, 2H), 2.61 (d, J = 4.5 Hz, 3H), 2.58-2.23 (m, 2H), 2.18 (t , J = 7.4 Hz, 2H), 2.00-1.80 (m, 1H), 1.60-1.20 (m, 10H), 0.90-0.70 (m, 1H), 0.82 (d, J = 6.5 Hz, 3H), 0.75 ( d, J = 6.5 Hz, 3H).

(9) 5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The title compound (30.20 g, 21.8 mmol) of Example 1 (8) was suspended in a mixed solvent of water (50 mL) -methanol (50 mL) -THF (50 mL) and 2.4 N hydrochloric acid (50 mL). 50 ml) was added at room temperature. The mixture was stirred for 3 hours. Methanol and THF were distilled off from the reaction solution under reduced pressure, and the precipitate was isolated by filtration and washed with isopropyl alcohol and diisopropyl ether. The resulting precipitate was suspended in water (600 ml) and neutralized with sodium bicarbonate (1.84 g, 21.8 mmol). The resulting aqueous solution was purified on a synthetic adsorbent column (DIAION HP-20: water, 50% methanol aqueous solution), and the fractions eluted with a 50% aqueous methanol solution were isolated and concentrated under reduced pressure until a precipitate appeared. The residue was recrystallized from water-isopropyl alcohol to give the title compound (4.01 g, 27%) as white crystals.
[α] _D ²⁰ = -50.3 (c = 1.0, MeOH)
¹ H-NMR (DMSO-d ₆ ) δ 10.28 (br s, 1H), 8.57 (br s, 1H), 8.28 (d, J = 8.7 Hz, 1H), 7.90-7.70 (m, 5H), 7.17 ( d, J = 8.6 Hz, 2H), 6.53 (d, J = 8.6 Hz, 2H), 4.70-4.52 (m, 1H), 3.50-3.20 (m, 3H), 2.91 (dd, J = 13.5, 3.3 Hz , 1H), 2.72-2.58 (m, 1H), 2.61 (d, J = 4.5 Hz, 3H), 2.50-2.25 (m, 2H), 2.16 (t, J = 7.3 Hz, 2H), 1.90 (dd, J = 13.6, 3.6Hz, 1H), 1.50-1.20 (m, 4H), 0.90-0.65 (m, 1H), 0.82 (d, J = 6.5Hz, 3H), 0.76 (d, J = 6.5Hz, 3H ).

Example 2 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid potassium salt

(1) 2-Tetrahydropyranyl-5-methyl-3 (R) - {1 (S) -methylcarbanoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamate potassium salt

To a solution of the title compound (5.00 g, 7.20 mmol) of Example 1 (7) in DMF (50 mL) successively N-methylmorpholine (1.58 mL, 14.39 mmol), O-2-tetrahydropyranylhydroxylamine (1.26 g, 10.80 mmol), HOBt · H ₂ O (1.10 g, 7.20 mmol) and Diisopropylcarbodiimide (1.36 g, 10.80 mmol, hereinafter abbreviated to DIPCI) was added under ice-cooling (internal temperature 10 ° C). The mixture was stirred for 21 hours while the temperature was gradually raised to room temperature. A solution of potassium acetate (0.71 g, 7.20 mmol) in acetic acid (10 ml) was added to the reaction solution, and after stirring the mixture for 1 hour, diisopropyl ether was added. The precipitate was isolated by filtration. The resulting precipitate was washed with diisopropyl ether and dried to give the title compound (5.82 g, quantitative determination) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 10.87 and 10.83 (br s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.90-7.70 (m, 5H), 7.18 (d, J = 8.6 Hz , 2H), 6.54 (d, J = 8.6 Hz, 2H), 4.70-4.55 (m, 1H), 4.53 and 4.38 (br s, 1H), 3.75-3.12 (m, 4H), 3.12-2.55 (m, 3H), 2.62 (d, J = 4.6Hz, 3H), 2.55-2.22 (m, 2H), 2.18 (t, J = 7.3Hz, 2H), 2.00-1.85 (m, 1H), 1.60-1.15 (m , 10H), 0.90-0.70 (m, 1H), 0.82 (d, J = 6.6 Hz, 3H), 0.75 (d, J = 6.6 Hz, 3H).

(2) 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid potassium salt

To a solution of the title compound (5.82 g, about 7.20 mmol) of Example 2 (1) in methanol (100 mL) was added a solution of 5% hydrogen chloride in methanol (50 mL) and the mixture became 1 , Stirred at 30 ° C for 5 h. Diisopropyl ether (450 ml) was added to the reaction solution, and the precipitate was isolated by filtration and washed with diisopropyl ether. The resulting precipitate was recrystallized from water-isopropyl alcohol to give the title compound (2.85 g, 58%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ 10.27 (br s, 1H), 8.55 (br s, 1H), 8.27 (d, J = 8.6 Hz, 1H), 7.90-7.70 (m, 5H), 7.17 ( d, J = 8.6 Hz, 2H), 6.53 (d, J = 8.6 Hz, 2H), 4.68-4.52 (m, 1H), 3.50-3.20 (m, 3H), 2.91 (dd, J = 13.9, 4.0 Hz , 1H), 2.75-2.60 (m, 1H), 2.61 (d, J = 4.6 Hz, 3H), 2.55-2.25 (m, 2H), 2.17 (t, J = 7.3 Hz, 2H), 1.94 (dd, J = 13.5, 3.6 Hz, 1H), 1.50-1.20 (m, 4H), 0.90-0.70 (m, 1H), 0.82 (d, J = 6.3 Hz, 3H), 0.76 (d, J = 6.3 Hz, 3H ).

Example 3

5-Methyl-3 (R) - {1 (R) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [a diastereoisomeric species of the compound of Example 1]

(1) N ^α - (tert-butoxycarbonyl) -D-tyrosine N-methylamide

The Synthesis was performed using N- (tert-butoxycarbonyl) -D-tyrosine and in the same manner as described in Example 1 (3) Procedure performed.

(2) D-tyrosine N-methylamide hydrochloride

The synthesis was carried out using the title compound of Example 3 (1) and in the same manner as in the method described in Example 1 (4).
[α] _D ²² = -73.1 (c = 1.0, H ₂ O)

(3) 5-methyl-3 (R) - {1 (R) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 1 (2) and the title compound of Example 3 (2) and in the same manner as in the method described in Example 1 (5) to (9).
¹ H-NMR (DMSO-d ₆ ) δ 10.43 (s, 1H), 8.66 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 4.8 Hz, 1H), 7.83 (s, 4H), 7.14 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 4.49-4.42 (m, 1H), 3.98 (dt, J = 13.0, 5.9 Hz, 2H), 4.02-3.94 (m, 1H), 3.48-3.38 (m, 1H), 3.00 (dd, J = 14.2, 4.2 Hz, 1H), 2.60 (d, J = 4.5 Hz, 3H), 2.00 (dt , J = 14.9, 6.5 Hz, 2H), 1.40 (app t, J = 10.4 Hz, 1H), 0.85-0.68 (m, 2H), 0.63 (d, J = 5.5 Hz, 3H), 0.59 (d, J = 5.6 Hz, 3H).

Example 4

5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [a diastereoisomeric species of the compound of Example 1]

(1) 4-tert-butoxy-2 (R) -isobutyl-3 (R or S) -phthalimidomethylbernsteinsäure

[a diastereoisomeric species of the compound of Example 1 (2)]

The title compound of Example 1 (2) was obtained by purification by column chromatography.
¹ H-NMR (DMSO-d ₆ ) δ 7.89-7.82 (m, 2H), 7.75-7.68 (m, 2H), 4.09 (dd, J = 15.4, 10.2 Hz, 1H), 3.83 (dd, J = 15.4 , 5.9 Hz, 1H), 3.15-3.07 (m, 1H), 2.82-2.74 (m, 1H), 1.79-1.60 (m, 2H), 1.54-1.38 (m, 1H), 1.32 (s, 9H), 0.94 (d, J = 7.4 Hz, 3H), 0.92 (d, J = 7.4 Hz, 3H).

(2) N ^α - (tert-butoxycarbonyl) - (O-3-sulfopropyl) -L-tyrosine-N-methylamidcium salt

To a solution of the title compound (10.00 g, 34.0 mmol) of Example 1 (3) and 1,3-propanesultone (4.56 g, 37.4 mmol) in DMF (100 mL) was cesium carbonate (12, 18 g, 37.4 mmol) at room temperature and the mixture was stirred for 15 h. Diisopropyl ether (300 ml) was added to the reaction solution and the precipitate was isolated by filtration, washed with ethyl acetate and dried to give the title compound (26.42 g, quantitative determination) as a brown solid.
¹ H-NMR (DMSO-d ₆ ) δ 7.90-7.75 (m, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 6.90-6.70 (m, 1H), 4.10-3.85 (m, 1H), 3.99 (t, J = 6.6 Hz, 2H), 2.84 (dd, J = 13.8, 4.8 Hz, 1H), 2.65 (dd, J = 13.8, 10.1 Hz, 1H ), 2.60-2.45 (m, 2H), 2.57 (d, J = 4.5Hz, 3H, 2.05-1.90 (m, 2H), 1.30 (s, 9H).

(3) O-3-sulfopropyl-L-tyrosine N-methylamide

The title compound (26.42 g, about 34.0 mmol) of Example 4 (2) was suspended in methylene chloride (50 mL), anisole (18.5 mL, 169.9 mmol) and trifluoroacetic acid (50 mL) were added under ice-cooling added to the suspension. The mixture was stirred for 1 h at the same temperature and for 1 h at room temperature. Diisopropyl ether (300 ml) was added to the reaction solution and the precipitate was isolated by filtration, washed with ethyl acetate and dried to give a crude product (35.96 g) as a pale brown solid. This was recrystallized from water (35 ml) - isopropyl alcohol (150 ml) to give the title compound (8.00 g, 74%) as white crystals.
[α] _D ²⁵ = + 55.4 (C = 1.0, H ₂ O).
¹ H-NMR (DMSO-d ₆ ) δ 8.40-7.80 (br, 3H), 8.30 (q, J = 4.5 Hz, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.05 (t, J = 6.5 Hz, 2H), 3.83 (dd, J = 7.2, 6.6 Hz, 1H), 2.97 (dd, J = 13.8, 6.6 Hz, 1H), 2.86 (dd, J = 13.8, 7.2Hz, 1H), 2.61 (d, J = 4.5Hz, 3H), 2.55 (t, J = 7.2Hz, 3H), 2.10-1.90 (m, 2H).

(4) tert -butyl-5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanoate sodium salt

To a solution of the title compound (1.54 g, 3.95 mmol) of Example 4 (1) and the title compound (1.70 g, 3.95 mmol) of Example 4 (3) in DMF (30 mL) were added sequentially HOBt · H ₂ O (0.61 g, 3.95 mmol), N-methylmorpholine (1.73 mL, 15.7 mmol) and WSCl · HCl (0.91 g, 4.74 mmol) under ice-cooling (internal temperature 10 ° C), and the mixture was stirred for 8 hours, gradually raising the temperature to room temperature. The reaction solution was poured into ice-water, and sodium dihydrogen phosphate dihydrate (1.85 g, 11.85 mmol) was added. The mixture was saturated with sodium chloride and extracted (100 ml x 3) with a solvent mixture of THF-methanol (10/1). To the extract solution was added butanol, and the mixture was concentrated under reduced pressure. Diisopropyl ether was added to the residue and the precipitate was isolated by filtration and dried to give the title compound (1.62 g, 58%) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 8.13 (d, J = 8.1 Hz, 1H), 7.95-7.83 (m, 4H), 7.70 (d, J = 4.5 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 4.35-4.32 (m, 1H), 3.96 (t, J = 6.6 Hz, 2H), 3.82-3.64 (m, 1H), 3.00- 2.90 (m, 1H), 2.89-2.73 (m, 1H), 2.70-2.60 (m, 1H), 1.95 (dt, J = 14.7, 7.8 Hz, 2H), 1.57 (m, 1H), 1.42-1.28 ( m, 1H), 1.13 (s, 9H), 0.86 (d, J = 6.0 Hz, 3H), 0.81 (d, J = 6.0 Hz, 3H).

(5) 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanoic acid

The title compound (1.62 g, 2.28 mmol) of Example 4 (4) was suspended in methylene chloride (10 ml), and trifluoroacetic acid (10 ml) was added under ice-cooling (internal temperature 5 ° C). The mixture was stirred at room temperature for 3 hours. Ether was added to the reaction solution under ice-cooling, and the precipitate was isolated by filtration to give the title compound (1.41 g, quantitative determination) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 8.36 (d, J = 8.1 Hz, 1H), 7.92-7.83 (m, 4H), 7.72 (d, J = 4.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 4.39 (dd, J = 15.0, 7.8 Hz, 1H), 3.92-3.87 (m, 2H), 2.96-2.67 (m, 4H), 1.85 (dt, J = 14.4, 6.9 Hz, 2H), 1.55 (m, 1H), 0.84 (d, J = 6.0 Hz, 3H), 0.80 (d, J = 6.0 Hz, 3H).

(6) O- (2-nitrobenzyl) -5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or R) S) -phthalimidomethylhexanohydroxamatnatriumsalz

To a solution of the title compound (1.41 g, 2.23 mmol) of Example 4 (5) in DMF (20 mL) was sequentially added N-methylmorpholine (1.0 mL, 9.80 mmol), O-2-nitrobenzylhydroxylamine hydrochloride (0.55 g, 2.67 mmol), HOBt · H ₂ O (0.34 g, 2.23 mmol) and WSCl · HCl (0.51 g, 2.67 mmol) under ice-cooling (internal temperature 10 ° C ), and the mixture was stirred for 48 hours, gradually raising the temperature to room temperature. The reaction solution was poured into ice-water, and sodium dihydrogen phosphate dihydrate (1.04 g, 6.69 mmol) was added. The mixture was saturated with sodium chloride and extracted with a solvent mixture of THF-methanol (10/1) (100 ml × 3). Butanol was added to the extract solution and the mixture was concentrated under reduced pressure. Diisopropyl ether was added to the residue and the precipitate was isolated by filtration and dried to give the title compound (0.35 g, 19%) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 11.39 (s, 1H), 8.14 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.81-7.76 (m, 5H) , 7.64-7.62 (m, 2H), 7.54-7.51 (m, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 5.04 (d, J = 14.7 Hz, 1H), 5.00 (d, J = 14.7 Hz, 1H), 4.33-4.30 (m, 1H), 3.92 (t, J = 6.6 Hz, 2H), 3.73-3.62 (m, 1H), 3.52-3.41 (m, 1H), 2.97-2.78 (m, 2H), 1.90 (dt, J = 14.4, 7.2 Hz, 2H), 1.52 (m, 1H), 1.28-1.26 (m, 2H), 0.78 (app d, J = 2.7 Hz, 6H).

(7) 5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The title compound (350 mg, 0.435 mmol) of Example 4 (6) was suspended in a solvent mixture of THF-water (9/1) and subjected to light irradiation with a high-pressure mercury vapor lamp under ice-cooling for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol and ether was added to allow precipitation. The precipitate was recrystallized (diisopropyl alcohol-water) to give the title compound (93 mg, 32%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ 10.58 (s, 1H), 8.75 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.89-7.66 (m, 4H), 7.06 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 6.3 Hz, 2H), 4.37-4.29 (m, 1H), 3.94 (t, J = 6.4 Hz, 2H), 3.75 (dd, J = 14.0, 10.3 Hz, 1H), 3.49 (dd, J = 13.6, 4.0 Hz, 1H), 2.92 (dd, J = 14.0, 6.1 Hz, 1H), 2.84-2.73 (m, 2H), 2.56 (d, J = 4.5 Hz , 3H), 2.54-2.42 (m, 2H), 1.90 (dt, J = 14.8, 7.1 Hz, 2H), 1.57 (app t, J = 9.4 Hz, 1H), 1.23-1.20 (m, 2H), 0.76 (app d, 3 = 4.5 Hz, 6H).

Example 5

5-methyl-3 (R) - {1 (R) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [a diastereoisomeric species of the compound of Example 1]

(1) N ^α - (tert-butoxycarbonyl) - (O-3-sulfopropyl) -D-tyrosine N-methylamide

The Synthesis was performed using the title compound of Example 3 (1) and in the same manner as described in Example 4 (2) Procedure performed.

(2) O-3-sulfopropyl-D-tyrosine N-methylamide

The synthesis was carried out using the title compound of Example 5 (1) and in the same manner as in the method described in Example 4 (3).
[α] _D ²⁷ = -55.5 (C = 1.0, H ₂ O)

(3) 5-Methyl-3- (R) - {1 (R) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 4 (1) and the title compound of Example 5 (2) and in the same manner as in the method described in Example 4 (4) - (7).
¹ H-NMR (DMSO-d ₆ ) δ 10.62 (s, 1H), 9.20 (s, 1H), 8.40 (d, J = 8.7 Hz, 1H), 7.88-7.82 (m, 4H), 7.51 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.77 (d, J 8.4 Hz, 2H), 4.29-4.23 (m, 1H), 3.97 (t, J = 6.4 Hz, 2H ), 3.76 (dd, J = 13.7, 9.0 Hz, 1H), 3.56 (dd, J = 13.7, 4.4 Hz, 1H), 3.26-3.13 (m, 1H), 2.63 (d, J = 4.4 Hz, 3H) , 2.56-2.49 (m, 2H), 2.44-2.32 (m, 1H), 1.96 (dt, J = 15.0, 6.4 Hz, 2H), 1.29-1.24 (m, 2H), 0.72 (d, J = 5.8 Hz , 3H), 0.57-0.44 (m, 1H), 0.56 (d, J = 5.5 Hz, 3H).

Example 6

5-Methyl-3 (S) - {1 (R) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [Optical isomer of the compound of Example 1]

(1) 1,2-Dibenzyl-1-tert-butyl-4-methyl-1,1,2- (S) -pentanetricarboxylate

The Synthesis was performed using (L) -leucine as the starting material and in the same manner as described in Example 1 (1) Procedure performed.

(2) 4-tert-butoxy-2 (S) -isobutyl-3 (R or S) -phthalimidomethylbernsteinsäure

The Synthesis was performed using the title compound of Example 6 (1) and in the same manner as described in Example 1 (2) Procedure performed.

(3) 5-Methyl-3 (S) - {1 (R) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 6 (2) and the title compound of Example 3 (2) and in the same manner as in the method described in Example 1 (5) - (9).
[α] _D ²⁰ = +46.5 (c = 1.02, MeOH)

The NMR data agreed with the NMR data of the title compound of Example 1 (9) match.

Example 7

5-Methyl-3 (S) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [a diastereoisomeric species of the compound of Example 1]

The synthesis was carried out using the title compound of Example 6 (2) and the title compound of Example 1 (4) and in the same manner as in the method described in Example 1 (5) - (9) leads.

The NMR data agreed with the NMR data of the title compound of Example 3 (3) match.

Example 8

5-Methyl-3 (S) - {1 (R) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [a diastereoisomeric species of the compound of Example 1]

(1) 4-tert-butoxy-2 (S) -isobutyl-3 (R or S) -phthalimidomethylbernsteinsäure

[a diastereoisomeric species of the compound of Example 6 (2)]

The Title compound of Example 6 (2) was purified by purification using column receive. The NMR data were consistent with the NMR data of the title compound of Example 4 (1).

(2) 5-Methyl-3 (S) - {1 (R) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The Synthesis was performed using the title compound of Example 8 (1) and the title compound of Example 5 (2) and the same As in the method described in Example 4 (4) - (7).

The NMR data agreed with the NMR data of the title compound of Example 4 (7) match.

Example 9

5-Methyl-3 (S) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [a diastereoisomeric species of the compound of Example 1]

The Synthesis was performed using the title compound of Example 8 (1) and the title compound of Example 4 (3) and the same The manner described in Example 4 (4) - (7) is performed. The NMR data agreed with the NMR data of the title compound of Example 5 (3) match.

Example 10 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (2-sulfoethoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

(1) N ^α - (tert-butoxycarbonyl) - (O-2-benzyloxyethyl) -L-tyrosine N-methylamide

To a solution of the title compound (5.00 g, 16.99 mmol) of Example 1 (3) in THF (150 mL) was added sequentially ethylene glycol monobenzyl ether (7.76 g, 50.96 mmol), triphenylphosphine (13.37 g, 50.96 mmol) and diethyl azodicarboxylate (40% toluene solution) (22.19 g, 50.96 mmol) under ice-cooling. The mixture was stirred for 2 hours at this temperature and for 68 hours at room temperature. The reaction solution was concentrated under reduced pressure and purified by flush chromatography on a silica gel column (silica gel 150 g, hexane / ethyl acetate = 5/1, 2/1, 1/1) to give the title compound (7.86 g) as white solid was obtained.
¹ H-NMR _(CDCl3) δ 7:45 to 7:25 (m, 5H), 7.10 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.90-5.50 (br, 1H) , 5.20-4.85 (br, 1H), 4.63 (s, 2H), 4.30-4.15 (m, 1H), 4.13 (t, J = 4.8 Hz, 2H), 3.82 (t, J = 4.8 Hz, 2H), 3.03 (dd, J = 13.7, 6.2 Hz, 1H), 2.93 (dd, J = 13.7, 7.7 Hz, 1H), 2.71 (d, J = 4.8 Hz, 3H), 1.41 (s, 9H).

(2) N ^α - (tert-butoxycarbonyl) - (O-2-hydroxyethyl) -L-tyrosine-N-methylamide

To a solution of the title compound (7.86 g, about 11.55 mmol) of Example 10 (1) in ethanol (300 ml) was added under ice-cooling and under a nitrogen atmosphere palladium black (0.80 g). After hydrogen substitution, the mixture was stirred for 6 hours at room temperature. The catalyst was removed from the reaction solution by filtration on celite and the residue was concentrated under reduced pressure. The resulting residue was purified by flush chromatography on a silica gel column (silica gel 200 g, chloroform / methanol = 50/1, 20/1, 10/1) to give the title compound (2.48 g, yield after two stages of Example 10 (1): 43%) as a white solid.
¹ H-NMR _(CDCl3) δ 7.11 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.00-5.60 (br, 1H), 5.30-4.80 (br, 1H) , 4.35-4.20 (m, 1H), 4.06 (t, J = 4.4 Hz, 2H), 4.02-3.90 (m, 2H), 3.02 (dd, J = 13.4, 6.3 Hz, 1H), 2.95 (dd, J = 13.4, 7.5 Hz, 1H), 2.73 (d, J = 4.8 Hz, 3H), 2.15 (t, J = 6.0 Hz, 1H), 1.41 (s, 9H).

(3) N ^α - (tert-butoxycarbonyl) - (O-2-bromoethyl) -L-tyrosine-N-methylamide

To a solution of the title compound (2.48 g, 7.33 mmol) of Example 10 (2) in methylene chloride (50 ml) was added sequentially triphenylphosphine (2.88 g, 10.99 mmol) and carbon tetrabromide (2.92 g, 8.79 mmol) at room temperature. The mixture was stirred at the same temperature for 15 minutes. Saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the reaction solution, and the mixture was extracted with chloroform (100 ml). The obtained organic layer was washed with water (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by flush chromatography on a silica gel column (silica gel 100 g, chloroform / methanol = 50/1, 20/1) to give the title compound (4.11 g) as a white solid.
¹ H-NMR _(CDCl3) δ 7.11 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.10-5.60 (br, 1H), 5.30-4.80 (br, 1H) , 4.30-4.15 (m, 1H), 4.26 (t, J = 6.3 Hz, 2H), 3.63 (t, J = 6.3 Hz, 2H), 3.10-2.90 (m, 2H), 2.73 (d, J = 5.1 Hz, 3H), 1.41 (s, 9H).

(4) N ^α - (tert-butoxycarbonyl) - (O-2-sulfoethyl) -L-tyrosine N-methylamide sodium salt

The title compound (4.11 g, about 6.11 mmol) of Example 10 (3) was suspended in a solution of ethanol (100 ml) -water (50 ml) and heated to 80 ° C to dissolve. A solution of sodium sulfite (0.85 g, 6.72 mmol) in water (50 mL) was added and the mixture was stirred at reflux for 22 h. The reaction solution was cooled, and ethanol was distilled off under reduced pressure. The residue was washed with ethyl acetate (100 ml). Butanol was added to the resulting aqueous layer, and the mixture was concentrated under reduced pressure to give the title compound (1.65 g, yield after two stages of Example 10 (3): 56%) as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ 7.90-7.75 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.95-6.80 (m, 1H), 4.16 (t, J = 7.7Hz, 2H), 4.10-3.90 (m, 1H), 2.88 (t, J = 7.7Hz, 2H), 2.95-2.75 (m, 1H), 2.75-2.60 (m , 1H), 2.57 (d, J = 4.5 Hz, 3H), 1.30 (s, 9H).

(5) O-2-sulfoethyl-L-tyrosine N-methylamide

A solution of the title compound (1.65 g, about 4.10 mmol) of Example 10 (4) in trifluoroacetic acid (20 ml) was stirred for 1 h at room temperature. Toluene was added to the reaction solution, and the mixture was concentrated under reduced pressure to give the title compound (2.54 g, quantitative determination).
¹ H-NMR (DMSO-d ₆ ) δ 8.40-8.25 (m, 1H), 8.35-7.90 (br, 3H), 7.13 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.20 (t, J = 7.6 Hz, 2H), 4.00-3.70 (m, 1H), 3.10-2.80 (m, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.61 (d, J = 4.8 Hz, 3H).

(6) tert -butyl-5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (2-sulfoethoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanoate sodium salt

To a solution of the title compound (1.60 g, 4.10 mmol) of Example 1 (2) and the title compound (2.54 g, about 4.10 mmol) of Example 10 (5) in DMF (20 mL) successively added HOBt-H ₂ O (0.63 g, 4.10 mmol), N-methylmorpholine (1.80 mL, 16.40 mmol) and WSCl · HCl (0.94 g, 4.92 mmol) under ice-cooling and the mixture was stirred for 24.5 hours as the temperature gradually increased to room temperature. The reaction solution was poured into a solution of sodium dihydrogen phosphate dihydrate (3.20 g, 20.50 mmol) dissolved in water (100 ml), and washed with ethyl acetate (100 ml). The resulting aqueous layer was saturated with sodium chloride and extracted with a solution of THF-methanol (10/1) (100 ml x 3). Butanol was added to the extract solution and the mixture was concentrated under reduced pressure. Methanol was added to the residue obtained, and an insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (2.61 g, 91%) as a yellow solid.
¹ H-NMR (DMSO-d ₆ ) δ 8.45 (d, J = 8.9 Hz, 1H), 8.00-7.80 (m, 5H), 7.19 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 8.6 Hz, 2H), 4.75-4.60 (m, 1H), 3.80-3.60 (m, 2H), 3.30-3.15 (m, 1H), 3.00-2.90 (m, 1H), 2.80-2.40 (m, 3H) , 2.62 (d, J = 4.5Hz, 3H), 2.35-2.15 (m, 2H), 2.00-1.85 (m, 1H), 1.60-1.20 (m, 2H), 1.09 (s, 9H), 0.90-0.75 (m, 1H), 0.85 (d, J = 6.4 Hz, 3H), 0.76 (d, J = 6.4 Hz, 3H).

(7) 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (2-sulfoethoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanoic acid

The title compound (2.61 g, 3.75 mmol) of Example 10 (6) was suspended in trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 4 hours. Diethyl ether (100 ml) was added to the reaction solution and the precipitate was isolated by filtration to give the title compound (2.20 g, 95%) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 13.00-11.60 (br, 1H), 8.41 (d, J = 8.7 Hz, 1H), 8.00-7.75 (m, 5H), 7.18 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 8.6Hz, 2H), 4.75-4.60 (m, 1H), 3.78-3.60 (m, 2H), 3.22 (dd, J = 13.6, 11.3Hz, 1H), 2.94 (dd , J = 13.8, 4.0 Hz, 1H), 2.75-2.60 (m, 1H), 2.62 (d, J = 4.4 Hz, 3H), 2.60-2.42 (m, 2H), 2.30-2.15 (m, 2H), 2.02 (dd, J = 13.6, 4.1 Hz, 1H), 1.60-1.40 (m, 1H), 1.40-1.20 (m, 1H), 0.90-0.70 (m, 1H), 0.84 (d, J = 6.5 Hz, 3H), 0.76 (d, J = 6.5 Hz, 3H).

(8) 2-Tetrahydropyranyl-5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (2-sulfoethoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamate sodium salt

To a solution of the title compound (2.20 g, 3.56 mmol) of Example 10 (7) in DMF (50 ml) was added N-methylmorpholine (0.78 ml, 7.12 mmol), O-2, under ice-cooling successively -Tetrahydropyranylhydroxylamine (0.50g, 4.27mmol), HOBt · H ₂ O (0.55g, 3.56mmol) and WSCl · HCl (0.82g, 4.27mmol) were added, and the Mi The mixture was stirred for 16 h while the temperature was gradually raised to room temperature. The reaction solution was poured into a solution of sodium dihydrogen phosphate dihydrate (2.78 g, 17.81 mmol) in water (200 ml) saturated with sodium chloride and extracted with a solvent mixture of THF-methanol (10/1) (200 ml × 1 , 100 ml × 3). Butanol was added to the extract solution and the mixture was concentrated under reduced pressure. Diethyl ether was added to the residue and the precipitate was isolated by filtration and dried to give the title compound (4.50 g, quantitative determination) as a white solid.
¹ H-NMR (DMSO-d6) δ 10.89 and 10.84 (br s, 1H), 8.37 (d, J = 9.0 Hz, 1H), 8.00-7.87 (m, 1H), 7.87-7.75 (m, 4H), 7.19 (d, J = 8.3Hz, 2H), 6.52 (d, J = 8.3Hz, 2H), 4.70-4.58 (m, 1H), 4.53 and 4.37 (br s, 1H), 3.75-3.25 (m, 3H ), 3.25-3.12 (m, 1H), 3.12-2.88 and 2.75-2.60 (m, 3H), 2.61 (d, J = 4.5Hz, 3H), 2.60-2.10 (m, 4H), 1.90-1.75 (m , 1H), 1.60-1.20 (m, 8H), 0.90-0.70 (m, 1H), 0.82 (d, J = 6.5 Hz, 3H), 0.75 (d, J = 6.5 Hz, 3H).

(9) 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (2-sulfoethoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The title compound (4.50 g, about 3.56 mmol) of Example 10 (8) was suspended in a solution of water (20 mL) -methanol (40 mL) -THF (40 mL), and 1 N hydrochloric acid (20 ml) was added. The mixture was stirred at room temperature for 15 hours, and methanol and THF were distilled off from the reaction solution under reduced pressure. Water (300 ml) and 1N aqueous sodium bicarbonate solution (20 ml) were added to the residue for neutralization. The resulting solution was purified by reversed-phase column chromatography (Fuji Silysia Chemical Chromatorex ODS DM-1020T: 70 g, water / methanol = 100/0, 10/1, 5/1), butanol was added to the eluate, and the mixture was concentrated under reduced pressure. The residue was recrystallized from water-isopropanol to give the title compound (0.73 g, 31%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ 10.27 (br s, 1H), 8.57 (br s, 1H), 8.28 (d, J = 8.7 Hz, 1H), 7.95-7.75 (m, 5H), 7.18 ( d, J = 8.6 Hz, 2H), 6.52 (d, J = 8.6 Hz, 2H), 4.75-4.55 (m, 1H), 3.75-3.54 (m, 2H), 3.28 (dd, J = 13.5, 11.3 Hz , 1H), 2.92 (dd, J = 13.6, 3.9 Hz, 1H), 2.72-2.55 (m, 1H), 2.61 (d, J 4.5 Hz, 3H), 2.50-2.28 (m, 2H), 2.28-2.10 (m, 2H), 1.84 (dd, J = 13.5, 3.9Hz, 1H), 1.50-1.20 (m, 2H), 0.90-0.70 (m, 1H), 0.82 (d, J = 6.5Hz, 3H), 0.76 (d, J = 6.5 Hz, 3H).

Example 11 5-Methyl-3 (R) - {1- (S) -methylcarbamoyl-2- [4- (4-sulfobutoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

(1) N ^α - (tert-butoxycarbonyl) - (O-4-sulfobutyl) -L-tyrosine N-methylamidcium salt

The Synthesis was performed using the title compound of Example 1 (3) and 1,4-butane sultone and in the same manner as in Example 4 (2).

(2) O-4-sulfobutyl-L-tyrosine N-methylamide

The synthesis was carried out using the title compound of Example 11 (1) and in the same manner as in the method described in Example 4 (3).
¹ H-NMR (DMSO-d ₆ ) δ 8.40-8.25 (m, 1H), 8.40-7.90 (br, 3H), 7.11 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.10-3.70 (m, 3H), 3.05-2.78 (m, 2H), 2.61 (d, J = 4.6Hz, 3H), 2.55-2.35 (m, 2H), 1.90-1.50 (m, 4H) ,

(3) 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (4-sulfobutoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 1 (2) and the title compound of Example 11 (2) and in the same manner as in the method described in Example 10 (6) - (9).
¹ H-NMR (DMSO-d ₆₎ δ 10.27 (br s, 1H), 8:56 (br.s, 1H), 8.28 (d, J = 9.0 Hz, 1H), 7.95-7.75 (m, 5H), 7.18 (d, J = 8.6 Hz, 2H), 6.54 (d, J = 8.6 Hz, 2H), 4.70-4.55 (m, 1H), 3.45-3.15 (m, 3H), 2.92 (dd, J = 13.4, 3.2 Hz, 1H), 2.72-2.55 (m, 1H), 2.62 (d, J = 4.6 Hz, 3H), 2.50-2.38 (m, 1H), 2.38-2.25 (m, 1H), 2.21 (t, J = 7.8Hz, 2H), 1.81 (dd, J = 13.5, 3.8Hz, 1H), 1.50-1.20 (m, 4H), 1.10-0.85 (m, 2H), 0.85-0.70 (m, 1H), 0.83 (i.e. , J = 6.5 Hz, 3H), 0.75 (d, J = 6.5 Hz, 3H).

Example 12 5-Methyl-3 (R) - {1- (S) -methylcarbamoyl-2- [4- (5-sulfopentoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

(1) Na- (tert-butoxycarbonyl) - (O-5-chloropentyl) -L-tyrosine N-methylamide

A solution of the title compound (10.00 g, 34.0 mmol) of Example 1 (3), 1-bromo-5-chloropentane (5.0 mL, 38.0 mmol), K ₂ CO ₃ (2.36 g , 17.1 mmol) in DMF (100 ml) was stirred at 70 ° C for 22 h. After allowing to cool, the solvent was distilled off under reduced pressure, and water was added. The mixture was extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography on silica gel (CHCl ₃ ) to give the title compound (7.56 g, 56%).
¹ H-NMR (DMSO-d ₆ ) δ 7.99-7.74 (m, 1H), 7.12 (d, J = 8.4 Hz, 2H), 6.83 (m, 1H), 6.81 (d, J = 8.4 Hz, 2H) , 4.11-3.99 (m, 1H), 3.92 (t, J = 6.3 Hz, 2H), 3.65 (t, J = 6.6 Hz, 2H), 2.89-2.75 (m, 1H), 2.74-2.45 (m, 1H ), 2.59 (m, 3H), 1.90-1.43 (m, 6H), 1.35-1.15 (m, 9H).

(2) N ^α - (tert-butoxycarbonyl) - (O-5-sulfopentyl) -L-tyrosine N-methylamide sodium salt

The synthesis was carried out using the title compound of Example 12 (1) and in the same manner as in the method described in Example 10 (4).
¹ H-NMR (DMSO-d ₆ ) δ 7.95-7.75 (br, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.87-6.83 (m, 1H), 6.81 (d, J = 8.4 Hz, 2H), 4.50-4.21 (br, 1H), 4.10-3.98 (m, 1H), 3.98-3.77 (m, 2H), 2.92-2.78 (m, 1H), 2.70-2.45 (m, 1H), 2.59 ( m, 3H), 2.44-2.30 (m, 2H), 1.79-1.36 (m, 6H), 1.35-1.15 (m, 8H).

(3) O-5-sulfopentyl-L-tyrosine N-methylamide

The synthesis was carried out using the title compound of Example 12 (2) and in the same manner as in the method described in Example 10 (5).
¹ H-NMR (DMSO-d ₆ ) δ 8.35-8.24 (br, 1H), 8.22-8.01 (br, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 3.93 (t, J = 6.3 Hz, 2H), 3.90-3.74 (m, 1H), 3.66-3.52 (m, 1H), 3.50-3.30 (m, 2H), 3.07-2.79 (m, 1H) , 2.62 (d, J = 4.5 Hz, 2H), 2.45-2.32 (m, 1H), 1.80-1.39 (m, 7H).

(4) 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (5-sulfopentoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 1 (2) and the title compound of Example 12 (3) and in the same manner as in the method described in Example 10 (6) - (9).
¹ H-NMR (DMSO-d ₆ ) δ 10.27 (br, 1H), 8.56 (br, 1H), 8.28 (d, J = 9.0 Hz, 1H), 7.88-7.80 (br, 5H), 7.19 (d, J = 8.7Hz, 2H), 6.53 (d, J = 8.7Hz, 2H), 4.67-4.57 (m, 1H), 3.40-3.18 (m, 4H), 2.98-2.81 (m, 1H), 2.70-2.51 (m, 4H), 2.49-2.37 (m, 1H), 2.36-2.21 (m, 2H), 1.85-1.71 (m, 1H), 1.48-1.20 (m, 4H), 1.08-0.82 (m, 5H) , 0.82 (d, J = 6.3 Hz, 3H), 0.75 (d, J = 6.3 Hz, 3H).

Example 13 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) - (2-naphthylmethyl) hexanohyroxamic acid sodium salt

(1) 4-tert-butoxy-2 (R) -isobutyl-3 (R or S) - (2-naphthyl) methyl succinic acid

The synthesis was carried out using the title compound of Example 1 (1) and 2-naphthylbromide and in the same manner as in the method described in Example 1 (2). For purification, flush column chromatography and recrystallization (hexane) were carried out.
¹ H-NMR _(CDCl3) δ 7.80-7.73 (m, 3H), 7.61 (s, 1H), 7:47 to 7:39 (m, 2H), 7.28 (d, J = 1.8 Hz, 1H), 3.07-2.95 ( m, 3H), 2.82 (m, 1H), 1.82-1.72 (m, 2H), 1.65-1.62 (m, 1H), 1.22 (s, 9H), 0.93 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.3 Hz, 3H).

(2) 5-Methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) - (2-naphthylmethyl) hexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 13 (1) and the title compound of Example 4 (3) and in the same manner as in the method described in Example 10 (6) - (9).
¹ H-NMR (DMSO-d ₆ ) δ 10.13 (br s, 1H), 8.56 (br s, 1H), 8.31 (d, J = 8.7 Hz, 1H), 7.90-7.65 (m, 4H), 7.50- 7.35 (m, 2H), 7.26 (s, 1H), 7.20 (d, J = 8.6 Hz, 2H), 6.94 (dd, J = 8.4, 1.5 Hz, 1H), 6.59 (d, 3 = 8.6 Hz, 2H ), 4.70-4.55 (m, 1H), 3.50-3.20 (m, 3H), 2.90 (dd, J = 13.6, 3.9 Hz, 1H), 2.72 (dd, J = 13.6, 11.5 Hz, 1H), 2.61 ( d, J = 4.5Hz, 3H), 2.58-2.40 (m, 1H), 2.30-2.20 (m, 1H), 2.20 (t, J = 7.3Hz, 2H), 1.94-1.80 (m, 1H), 1.60 -1.20 (m, 4H), 1.00-0.80 (m, 1H), 0.85 (d, J = 6.5 Hz, 3H), 0.77 (d, J = 6.5 Hz, 3H).

Example 14 5-Methyl-3 (R) - {1 (S) -phenylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

(1) N ^α - (tert-butoxycarbonyl) - (O-tert-butyl) -L-tyrosine-N-phenylamide

The synthesis was carried out using N- (tert-butoxycarbonyl) - (O-tert-butyl) -L-tyrosine and aniline and in the same manner as in the method described in Example 1 (3).
¹ H-NMR (DMSO-d ₆ ) δ 9.96 (br s, 1H), 7.56 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 8.3 Hz, 2H), 4.40-4.12 (m, 1H), 2.93 (dd, J = 13.4, 4.8 Hz, 1H), 2.80 (dd, J = 13.4, 10.1 Hz, 1H), 1.32 (s, 9H), 1.24 (s, 9H).

(2) L-tyrosine N-phenylamide hydrochloride

The synthesis was carried out using the title compound of Example 14 (1) and in the same manner as in the method described in Example 1 (4).
¹ H-NMR (DMSO-d ₆ ) δ 10.71 (br s, 1H), 9.37 (br s, 1H), 8.60-8.10 (br, 3H), 7.57 (d, J = 7.5 Hz, 2H), 7.34 ( t, J = 8.0 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 4.30-4.05 ( m, 1H), 3.09 (dd, J = 13.8, 6.6 Hz, 1H), 2.99 (dd, J = 13.8, 7.2 Hz, 1H).

(3) 5-Methyl-3 (R) - {1 (S) -phenylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 1 (2) and the title compound of Example 14 (2) and in the same manner as in the method described in Example 1 (5) - (9).
¹ H-NMR (DMSO-d ₆ ) δ 10.27 (br s, 1H), 10.11 (br s, 1H), 8.80-8.30 (br, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.90- 7.80 (m, 4H), 7.61 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 6.56 (d, J = 8.7 Hz, 2H), 4.90-4.80 (m, 1H), 3.50-3.20 (m, 3H), 3.04 (dd, J = 13.2, 3.6 Hz, 1H), 2.82 -2.68 (m, 1H), 2.60-2.45 (m, 1H), 2.42-2.29 (m, 1H), 2.16 (t, J = 7.4 Hz, 2H), 1.95 (dd, J = 13.6, 3.9 Hz, 1H ), 1.55-1.20 (m, 4H), 0.90-0.75 (m, 1H), 0.84 (d, J = 6.6 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H).

Example 15 5-Methyl-3 (R) - [2-phenyl-1 (S) - (sulfomethylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

(1) N- (tert-butoxycarbonyl) -L-phenylalanine benzyl ester

To a solution of N- (tert-butoxycarbonyl) -L-phenylalanine (30.0 g, 113 mmol) and benzyl alcohol (14.0 mL, 136 mmol) in methylene chloride (200 mL) was added 4-dimethylaminopyridine (1 , 38 g, 11.3 mmol) and WSCI · HCl (26.0 g, 136 mmol) and the mixture was stirred for 63 h, gradually increasing the temperature to room temperature. The solvent was distilled off from the reaction solution under reduced pressure, and water (200 ml) was added to the residue. The mixture was extracted with ethyl acetate (400 ml). The obtained extract solution was washed with 0.5 N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution, water and saturated brine (each 200 ml), and dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The obtained residue was recrystallized from hexane to give the title compound (33.1 g, 82%) as white crystals.
¹ H-NMR _(CDCl3) δ 7.45-6.90 (m, 10H), 5.17 (d, J = 12.3 Hz, 1H), 5.10 (d, J = 12.3 Hz, 1H), 5.05-4.85 (m, 1H) , 4.75-4.55 (m, 1H), 3.20-2.85 (m, 2H), 1.41 (s, 9H).

(2) L-phenylalanine benzyl ester hydrochloride

To a solution of the title compound (17.8 g, 50.1 mmol) of Example 15 (1) in chloroform (60 ml) was added, under ice-cooling, a 4N hydrochloric acid-dioxane solution (40 ml) and the mixture became 4 Stirred at room temperature for h. To the reaction solution was added diethyl ether (100 ml) and the precipitate was isolated by filtration, washed with diethyl ether and dried to give the title compound (13.7 g, 94%) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 8.75 (br s, 3H), 7.45-7.15 (m, 10H), 5.16 (d, J = 12.4 Hz, 1H), 5.11 (d, J = 12.4 Hz, 1H ), 4.32 (dd, J = 7.8, 5.6 Hz, 1H), 3.23 (dd, J = 14.0, 5.6 Hz, 1H), 3.09 (dd, J = 14.0, 7.8 Hz, 1H).

(3) tert -butyl-3 (R) - [1 (S) -benzyloxycarbonyl-2-phenylethylcarbamoyl] -5-methyl-2 (R or S) -phthalimidomethylhexanoate

To a solution of the title compound (10.0 g, 25.7 mmol) of Example 1 (2) and the title compound (7.49 g, 25.7 mmol) of Example 15 (2) in DMF (50 mL) were added successively under ice-cooling, N-methylmorpholine (8.5 mL, 77.0 mmol), HOBt · H ₂ O, 3.93 g, 25.7 mmol) and WSCI · HCl (5.91 g, 30.8 mmol), and the mixture was stirred for 14 hours, gradually raising the temperature to room temperature. The reaction solution was poured into ice-water (200 ml), and the precipitate was isolated by filtration. The resulting precipitate was dissolved in ethyl acetate (300 ml) and washed successively with 0.5 N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine (each 100 ml). It was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to give the title compound (12.3 g, 76%) as white crystals.
¹ H-NMR _(CDCl3) δ 7.90-7.80 (m, 2H), 7.80-7.68 (m, 2H), 7:40 to 7:05 (m, 10H), 6.70 (d, J = 8.2 Hz, 1H), 5.19 ( d, J = 12.2 Hz, 1H), 5.13 (d, J = 12.2 Hz, 1H), 5.04 (ddd, J = 8.6, 8.2, 5.5 Hz, 1H), 3.46 (dd, J = 14.2, 5.4 Hz, 1H ), 3.39 (dd, J = 14.2, 7.1 Hz, 1H), 3.30 (dd, J = 14.1, 5.5 Hz, 1H), 3.06 (dd, J = 14.1, 8.6 Hz, 1H), 2.86 (ddd, J = 9.7, 7.1, 5.4 Hz, 1H), 2.60 (ddd, J = 10.8, 9.8, 3.4 Hz, 1H), 1.70-1.55 (m, 1H), 1.55-1.35 (m, 1H), 1.25 (s, 9H) , 1.10-0.95 (m, 1H), 0.79 (d, J = 6.4 Hz, 3H), 0.78 (d, J = 6.4 Hz, 3H).

(4) 3 (R) - [1 (S) -Benzyloxycarbonyl-2-phenylethylcarbamoyl] -5-methyl-2 (R. or S) -phthalimidomethylhexanoic acid

To a solution of the title compound (12.0 g, 19.1 mmol) of Example 15 (3) in methylene chloride (10 ml) was added, under ice-cooling, trifluoroacetic acid (20 ml) and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off from the reaction solution under reduced pressure, and precipitation with diethyl ether-hexane was conducted, whereby the title compound (10.9 g, quantitative determination) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ 12.35 (br s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.95-7.80 (m, 4H), 7.45-7.20 (m, 7H), 7.20 -7.05 (m, 2H), 6.95-6.80 (m, 1H), 5.14 (d, J = 12.5 Hz, 1H), 5.09 (d, J = 12.5 Hz, 1H), 4.85-4.70 (m, 1H), 3.45-3.30 (m, 1H), 3.19 (dd, J = 13.7, 4.8 Hz, 1H), 2.89 (dd, J = 13.7, 11.0 Hz, 1H), 2.65 (ddd, J = 10.8, 5.1, 5.1 Hz, 1H), 2.59-2.38 (m, 2H), 1.60-1.40 (m, 1H), 1.40-1.20 (m, 1H), 0.90-0.75 (m, 1H), 0.74 (d, J = 6.6 Hz, 3H) , 0.69 (d, J = 6.6 Hz, 3H).

(5) 2-Tetrahydropyranyl-3 (R) - [1 (S) -benzyloxycarbonyl-2-phenylethylcarbamoyl] -5-methyl-2 (R. or S) -phthalimidomethylhexanohydroxamate

To a solution of the title compound (10.90 g, 19.1 mmol) of Example 15 (4) in DMF (50 mL) was sequentially added N-methylmorpholine (2.1 mL, 19.1 mmol), 2-tetrahydropyranylhydroxylamine (2 , 69g, 23.0mmol), HOBt · H ₂ O (2.93g, 19.1mmol) and WSCI · HCl (4.40g, 23.0mmol) under ice-cooling, and the mixture became 14 Stirred while the temperature was gradually raised to room temperature. The reaction solution was poured into ice-water (200 ml), and the precipitate was isolated by filtration. The resulting precipitate was washed with water and diethyl ether and dried to give the title compound (11.97 g, 93%) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 10.93 and 10.88 (br s, 1H), 8.70-8.55 (m, 1H), 7.95-7.75 (m, 4H), 7.40-7.20 (m, 7H), 7.15- 7.00 (m, 2H), 6.90-6.75 (m, 1H), 5.13 (d, J = 12.6Hz, 1H), 5.09 (d, J = 12.6Hz, 1H), 4.85-4.70 (m, 1H), 4.53 and 4.37 (br s, 1H), 3.75-3.27 (m, 2H), 3.19 (dd, J = 13.8, 4.8 Hz, 1H), 3.10-2.65 (m, 1H), 2.88 (dd, J = 13.8, 11.1 Hz, 1H), 2.60-2.35 (m, 2H), 2.24 (ddd, J = 13.9, 13.7, 4.1 Hz, 1H), 1.65-1.20 (m, 8H), 0.90-0.75 (m, 1H), 0.72 ( d, J = 6.3 Hz, 3H), 0.68 (d, J = 6.3 Hz, 3H).

(6) 2-Tetrahydropyranyl-3 (R) - [1 (S) -carboxy-2-phenylethylcarbamoyl] -5-methyl-2 (R or S) -phthalimidomethylhexanohydroxamate

The title compound (11.97 g, 17.9 mmol) of Example 15 (5) was dissolved in a mixed solvent of methanol (100 mL) -DMF (150 mL) and 10% palladium-carbon catalyst (1.20 g ) were added under ice-cooling. After hydrogen substitution, the mixture was stirred at room temperature for 3.5 hours. The catalyst was removed from the reaction solution by filtration on celite. The filtrate was concentrated under reduced pressure, and water was added to the obtained residue. The precipitate was isolated by filtration, washed with water and dried to give the title compound (9.17 g, 89%) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 13.50-11.50 (br, 1H), 10.93 and 10.88 (br s, 1H), 8.60-8.35 (m, 1H), 7.95-7.75 (m, 4H), 7.40- 7.20 (m, 2H), 7.15-7.00 (m, 2H), 6.87-6.70 (m, 1H), 4.70-4.57 (m, 1H), 4.53 and 4.37 (br s, 1H), 3.75-3.20 (m, 2H), 3.15 (dd, J = 13.7, 4.2 Hz, 1H), 3.10-2.65 (m, 1H), 2.81 (dd, J = 13.7, 11.5 Hz, 1H), 2.60-2.35 (m, 2H), 2.21 (ddd, J = 13.9, 13.7, 4.1 Hz, 1H), 1.70-1.10 (m, 8H), 0.95-0.70 (m, 1H), 0.82 (d, J = 6.3 Hz, 3H), 0.76 (d, J = 6.3 Hz, 3H).

(7) 2-Tetrahydropyranyl-5-methyl-3 (R) - [2-phenyl-1 (S) - (sulfomethylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamate sodium salt

To a solution of the title compound (5.79 g, 9.99 mmol) of Example 15 (6) in DMF (100 ml) was added successively under ice-cooling aminomethanesulfonic acid (1.33 g, 12.0 mmol), 3-hydroxy-3 4-dihydro-4-oxo-1,2,3-benzotriazine (1.63 g, 9.99 mmol, hereinafter abbreviated to HOOBt), N-methylmorpholine (1.1 mL, 9.99 mmol) and WSCI. HCl (2.30 g, 12.0 mmol). The mixture was stirred for 14 hours while the temperature was gradually raised to room temperature. The reaction solution was poured into a solution of sodium dihydrogen phosphate dihydrate (7.79 g, 49.9 mmol) in water (400 ml), saturated with sodium chloride and extracted with a solvent mixture of THF-methanol (10/1) (500 ml × 3). , Butanol was added to the extract solution and the mixture was concentrated under reduced pressure. Diisopropyl ether (1 L) was added to the residue and the precipitate was isolated by filtration and dried to give the title compound (37.80 g, quantified) as a white solid.
¹ H-NMR (DMSO-d ₆ ) δ 10.90-10.75 (m, 1H), 8.40-8.25 (m, 1H), 8.12-8.00 (m, 1H), 7.90-7.75 (m, 4H), 7.40-7.25 (m, 2H), 7.05-6.90 (m, 2H), 6.70-6.55 (m, 1H), 4.85-4.70 (m, 1H), 4.60-4.30 (m, 1H), 4.10-3.10 (m, 5H). , 3.10-2.20 (m, 5H), 2.00-1.80 (m, 1H), 1.70-1.15 (m, 8H), 0.95-0.70 (m, 1H), 0.83 (d, J = 6.3 Hz, 3H), 0.74 (d, J = 6.3 Hz, 3H).

(8) 5-Methyl-3 (R) - [2-phenyl-1 (S) - (sulfomethylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The title compound (37.80 g, about 9.99 mmol) of Example 15 (7) was suspended in a mixed solvent of water (200 mL) -methanol (400 mL) -THF (200 mL) and 1 N hydrochloric acid (200 ml) was added at room temperature. The mixture was stirred for 8 hours at the same temperature. Methanol and THF were distilled off from the reaction solution under reduced pressure. The precipitate was isolated by filtration and washed with isopropyl alcohol and diisopropyl ether. The resulting precipitate was suspended in water (250 ml) and neutralized with sodium bicarbonate (0.84 g, 9.99 mmol). The resulting aqueous solution was purified by means of a synthetic adsorbent column (DIAION HP-20: water, 50% aqueous methanol solution), and the fractions eluted with a 50% aqueous methanol solution were collected and concentrated under reduced pressure until precipitate occurred. The residue was recrystallized from water-isopropyl alcohol to give the title compound (1.37 g, 22%) as white crystals.
¹ H-NMR (DMSO-d ₆ ) δ 10.27 (br s, 1H), 8.56 (br s, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.10-7.95 (m, 1H), 7.95- 7.80 (m, 4H), 7.40-7.30 (m, 2H), 7.10-6.90 (m, 2H), 6.70-6.55 (m, 1H), 4.85-4.70 (m, 1H), 4.01 (dd, J = 13.0 , 6.6 Hz, 1H), 3.81 (dd, J = 13.0, 5.3 Hz, 1H), 3.50-3.20 (m, 1H), 3.12 (dd, J = 13.7, 3.2 Hz, 1H), 2.80-2.60 (m, 1H), 2.50-2.32 (m, 2H), 1.97-1.80 (m, 1H), 1.55-1.25 (m, 2H), 0.90-0.70 (m, 1H), 0.84 (d, J = 6.6 Hz, 3H) , 0.75 (d, J = 6.6 Hz, 3H).

Example 16

5-Methyl-3 (R) - [2-phenyl-1 (R) - (sulfomethylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [a diastereoisomeric species of the compound of Example 15]

(1) 2-Tetrahydropyranyl-5-methyl-3 (R) - [2-phenyl-1 (R) - (sulfomethylcarbamoyl) ethylcarbamoyl] -2 (R or S) - (phthalimidomethyl) hexanohydroxamate sodium salt

To a solution of the title compound (1.00 g, 1.73 mmol) of Example 15 (6) in DMF (20 mL) was sequentially added aminomethanesulfonic acid (0.23 g, 2.07 mmol), N-methylmorpholine (0.42 ml, 3.80 mmol), HOBt · H ₂ O (0.26 g, 1.73 mmol) and WSCl · HCl (0.40 g, 2.07 mmol) under ice-cooling, and the mixture was allowed to stand for 16 h stirred, the temperature was gradually increased to room temperature. A solution of sodium dihydrogen phosphate dihydrate (1.35 g, 8.63 mmol) in water (80 mL) was added to the reaction mixture and it was saturated with sodium chloride. The mixture was extracted with THF (100 ml x 3), and butanol was added to the extract solution. The mixture was concentrated under reduced pressure and diethyl ether was added to the residue. The precipitate was isolated by filtration and dried to give the title compound (1.27 g, quantitative determination, 28% de) as a white powder.

(2) 5-Methyl-3 (R) - [2-phenyl-1 (R) - (sulfomethylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid, sodium salt

The title compound (1.27 g, about 1.73 mmol, 28% de) of Example 16 (1) was suspended in a solution of water (25 mL) -methanol (60 mL) -THF (20 mL), and 1 N hydrochloric acid (10 ml) was added at room temperature. The mixture was stirred for 7 hours at the same temperature, and methanol and THF were distilled off from the reaction solution under reduced pressure. Water (20 ml) and sodium bicarbonate (1.00 g, 11.90 mmol) were added for neutralization. The resulting solution was purified by reverse phase column chromatography (Fuji Silysia Chemical Chromatorex ODS DM-1020T: 50 g, water / methanol = 100/0, 50/1, 20/1, 10/1, 5/1). The eluates from the latter half were collected, and methanol was distilled off under reduced pressure, followed by freeze-drying. The resulting freeze-dried product was precipitated from methanol-diethyl ether to give the title compound (0.24 g, 21%) as a white solid.
¹ H-NMR _(DMSO-d6) δ 10:39 (br s, 1H), 9:00 to 8:20 (br, 1H), 8:41 (d, J = 9.0 Hz, 1H), 8.18 (dd, J = 6.7, 5.2 Hz , 1H), 7.90-7.75 (m, 4H), 7.31 (d, J = 6.9 Hz, 2H), 7.24 (t, J = 7.2 Hz, 2H), 7.16 (t, J = 7.1 Hz, 1H), 4.75 -4.60 (m, 1H), 4.08-3.98 (m, 1H), 3.99 (dd, J = 12.9, 6.7 Hz, 1H), 3.77 (dd, J = 12.9, 5.2 Hz, 1H), 3.50-3.30 (m , 1H), 3.13 (dd, J = 13.9, 3.0 Hz, 1H), 2.70-2.58 (m, 1H), 2.69 (dd, J = 13.9, 11.8 Hz, 1H), 2.58-2.45 (m, 1H), 1.29 (t, J = 12.0 Hz, 1H), 0.81-0.65 (m, 1H), 0.65-0.50 (m, 1H), 0.54 (d, J = 5.1 Hz, 6H). Example 17 5-Methyl-3 (R) - [2-phenyl-1 (S) - (2-sulfoethylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 15 (6) and taurine and in the same manner as in the method described in Example 15 (7) - (8).
¹ H-NMR (DMSO-d ₆ ) δ 10.31 (br s, 1H), 8.59 (s, 1H), 8.38 (d, J = 8.7 Hz, 1H), 7.85-7.80 (br s, 5H), 7.29- 7.25 (m, 2H), 7.08-7.00 (m, 2H), 6.77-6.70 (m, 1H), 4.65-4.50 (m, 1H), 3.85-3.74 (m, 1H), 3.52-3.25 (m, 3H ), 3.07-2.93 (m, 1H), 2.85-2.70 (m, 1H), 2.55-2.40 (m, 3H), 2.19-2.10 (m, 1H), 1.55-1.29 (m, 2H), 0.90-0.70 (m, 1H), 0.82 (d, J = 6.3 Hz, 3H), 0.76 (d, J = 6.3 Hz, 3H).

Example 18

5-Methyl-3 (R) - [2-phenyl-1 (R) - (2-sulfoethylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [a diastereoisomeric species of the compound of Example 17]

The synthesis was carried out using the title compound of Example 15 (6) and taurine and in the same manner as in the method described in Example 16 (1) - (2).
¹ H-NMR _(DMSO-d6) δ 10:41 (br s, 1H), 8.70 (s, 1H), 8:43 (d, J = 8.4 Hz, 1H), 8:08 to 8:03 (1H, m), 7.83-7.80 (brs, 4H), 7.27-7.14 (m, 5H), 4.51-4.44 (m, 1H), 4.00-3.90 (m, 1H), 3.48-3.27 (m, 3H), 3.22-3.04 (m, 2H ), 2.85-2.55 (m, 5H), 1.65-1.30 (m, 1H), 0.85-0.54 (m, 8H).

Example 19 5-Methyl-3 (R) - [2-phenyl-1 (S) - (3-sulfopropylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 15 (6) and 3-aminopropanesulfonic acid and in the same manner as in the method described in Example 15 (7) - (8).
¹ H-NMR (DMSO-d ₆ ) δ 10.30 (s, 1H), 8.59 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 7.85-7.80 (br s, 5H), 7.31-7.27 (m, 2H), 7.07-7.00 (m, 2H), 6.73-6.65 (s, 1H), 4.68-4.55 (m, 1H), 3.85-3.73 (m, 1H), 3.25-2.95 (m, 3H) , 2.84-2.70 (m, 1H), 2.58-2.33 (m, 4H), 2.16-2.04 (m, 1H), 1.80-1.64 (m, 2H), 1.55-1.35 (m, 2H), 0.90-0.70 ( m, 1H), 0.83 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H).

Example 20

5-Methyl-3 (R) - [2-phenyl-1 (R) - (3-sulfopropylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [a diastereoisomeric species of the compound of Example 19]

The synthesis was carried out using the title compound of Example 15 (6) and 3-aminopropanesulfonic acid and in the same manner as in the method described in Example 16 (1) - (2).
¹ H-NMR (DMSO-d ₆ ) δ 10.40 (s, 1H), 8.62 (s, 1H), 8.40 (d, J = 8.7 Hz, 1H), 7.86-7.73 (br s, 4H), 7.32-7.05 (m, 5H), 4.60-4.48 (m, 1H), 4.02-3.89 (m, 1H), 3.82-3.69 (m, 1H), 3.68-3.30 (m, 2H), 3.25-3.00 (m, 3H) , 2.82-2.70 (m, 2H), 2.69-2.20 (m, 2H), 1.82-1.64 (m, 2H), 1.40-1.20 (m, 1H), 0.85-0.41 (m, 8H).

Example 21 5-Methyl-3 (R) - [2-phenyl-1 (S) - (4-sulfobutylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid, sodium salt

The synthesis was carried out using the title compound of Example 15 (6) and 4-aminobutanesulfonic acid in the same manner as in the method described in Example 15 (7) - (8).
¹ H-NMR (DMSO-d ₆ ) δ 10.31 (s, 1H), 8.59 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 7.84-7.80 (br s, 5H), 7.31-7.24 (m, 2H), 7.07-7.01 (m, 2H), 6.73-6.67 (s, 1H), 4.68-4.58 (m, 1H), 3.84-3.70 (s, 1H), 3.44-3.22 (m, 1H) , 3.15-2.84 (m, 3H), 2.89-2.71 (m, 1H), 2.51-2.32 (m, 3H), 2.17-2.03 (m, 1H), 1.70-1.20 (m, 6H), 0.90-0.70 ( m, 1H), 0.82 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H). Example 22 5-Methyl-3 (R) - [2-phenyl-1 (S) - (5-sulfopentylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid, sodium salt

(1) 5-bromopentylsulfonic acid sodium salt

To a solution of 1,5-dibromopentane (23.2 g, 101 mmol), ethanol (40 mL) and water (40 mL) was added dropwise a solution of sodium sulfite (4.24 g, 33 , 6 mmol) in water (15 ml). After refluxing for 2 hours, the solvent was distilled off under reduced pressure, and n-hexane / ethanol was added. The precipitated crystals were washed with n-hexane and dried in vacuo to give the title compound (3.81 g, 45%).
¹ H-NMR (DMSO-d ₆ ) δ 3.51 (t, J = 6.6 Hz, 2H), 2.46 (t, J = 7.5 Hz, 2H), 1.90-1.01 (m, 6H).

(2) 5-aminopentylsulfonic acid

Aqueous ammonia (50 ml) was added to the title compound (3.80 g, 15.0 mmol) of Example 22 (1). The mixture was stirred for 4 days at room temperature and dissolved in ethanol. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure and dried in vacuo to give the title compound (3.53 g, quantitative determination).
¹ H-NMR (DMSO-d ₆ ) δ 7.90-7.55 (br, 2H), 2.76 (t, J = 7.2 Hz, 2H), 2.39 (t, J = 7.8 Hz, 2H), 1.71-1.05 (m, 6H).

(3) 5-Methyl-3 (R) - [2-phenyl-1 (S) - (5-sulfopentylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 15 (6) and the title compound of Example 22 (2) and in the same manner as in the method described in Example 15 (7) - (8).
¹ H-NMR (DMSO-d ₆ ) δ 10.32 (s, 1H), 8.60 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.85-7.81 (br s, 5H), 7.77-7.72 (m, 1H), 7.30-7.26 (m, 2H), 7.08-7.02 (m, 2H), 6.76-6.70 (s, 1H), 4.70-4.58 (m, 1H), 3.50-3.30 (m, 1H) , 3.21-2.99 (m, 3H), 2.88-2.69 (m, 1H), 2.58-2.31 (m, 3H), 2.21-2.08 (m, 1H), 1.67-1.17 (m, 8H), 0.90-0.70 ( m, 1H), 0.82 (d, J = 6.3 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H).

Example 23 5-Methyl-3 (R) - [2-phenyl-1 (S) - (4-sulfophenylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 15 (6) and sulphanilic acid and in the same manner as in the method described in Example 15 (7) - (8).
¹ H-NMR _(DMSO-d6) δ 10:32 (br s, 1H), 15.10 (br s, 1H), 8.90-8.30 (br, 1H), 8:53 (d, J = 8.4 Hz, 1H), 8.00- 7.80 (m, 4H), 7.70-7.50 (m, 4H), 7.36 (d, J = 7.5 Hz, 2H), 7.07 (t, J = 7.5 Hz, 2H), 6.74 (t, J = 7.4 Hz, 1H ), 4.95-4.80 (m, 1H), 3.50-3.25 (m, 1H), 3.10 (dd, J = 13.6, 4.5 Hz, 1H), 2.86 (dd, J = 13.6, 11.1 Hz, 1H), 2.62- 2.37 (m, 2H), 2.19 (dd, J = 13.8, 3.8 Hz, 1H), 1.60-1.20 (m, 2H), 0.95-0.80 (m, 1H), 0.84 (d, J = 6.3 Hz, 3H) , 0.74 (d, J = 6.3 Hz, 3H).

Example 24

5-Methyl-3 (R) - [2-phenyl-1 (R) - (4-sulfophenylcarbamoyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid sodium salt [a diastereoisomeric species of the compound of Example 23]

The synthesis was carried out using the title compound of Example 15 (6) and sulphanilic acid and in the same manner as in the method described in Example 16 (1) - (2).
¹ H-NMR _(DMSO-d6) δ 10:45 (br s, 1H), 10.16 (br s, 1H), 8.68 (br s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 7.90-7.70 (m, 4H), 7.60 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 7.2 Hz, 2H), 7.27 (t, J = 7.4 Hz , 2H), 7.19 (t, J = 7.2 Hz, 1H), 4.85-4.65 (m, 1H), 4.04 (dd, J = 13.3, 10.8 Hz, 1H), 3.42 (dd, J = 13.3, 3.2 Hz, 1H), 3.18 (dd, J = 13.5, 3.3 Hz, 1H), 2.83 (dd, J = 13.5, 11.3 Hz, 1H), 2.80-2.40 (m, 2H), 1.50-1.30 (m, 1H), 0.95 -0.65 (m, 2H), 0.61 (d, J = 6.0 Hz, 3H), 0.59 (d, J = 6.0 Hz, 3H). Example 25 5-Methyl-2 (R or S) - (2-naphthylmethyl) -3 (R) - [2-phenyl-1 (S) - (sulfomethylcarbamoyl) ethylcarbamoyl] hexanohydroxamic acid, sodium salt

(1) 2-Tetrahydropyranyl-5-methyl-3 (R) - [1 (S) -carboxy-2-phenylethylcarbamoyl] -2 (R or S) - (2-naphthylmethyl) hexanohydroxamate sodium salt

The Synthesis was performed using the title compound of Example 13 (1) and the title compound of Example 15 (2) and the same As in the method described in Example 15 (3) - (6) carried out.

(2) 5-Methyl-2 (R or S) - (2-naphthylmethyl) -3 (R) - [2-phenyl-1 (S) - (sulfomethylcarbamoyl) ethylcarbamoyl] hexanohydroxamic acid sodium salt

The synthesis was carried out using the title compound of Example 25 (1) and aminomethane sulfonic acid and in the same manner as in the method described in Example 15 (7) - (8).
¹ H-NMR (DMSO-d ₆ ) δ 13.00-9.70 (br, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.20-8.07 (br, 1H), 7.85-7.69 (m, 3H), 7.50-7.29 (m, 4H), 7.28-7.19 (m, 1H), 7.13-7.00 (s, 2H), 6.99-6.84 (m, 1H), 6.82-6.60 (m, 1H), 4.99-4.68 (m , 1H), 4.10-3.94 (m, 1H), 3.93-3.75 (m, 1H), 3.07-2.98 (m, 1H), 2.75-2.69 (m, 1H), 2.52-2.30 (m, 3H), 2.29 -2.14 (m, 1H), 1.85-1.66 (m, 1H), 1.50-1.24 (m, 2H), 0.90-0.70 (m, 1H), 0.85 (d, J = 6.3 Hz, 3H), 0.75 (i.e. , J = 6.3 Hz, 3H). Example 26 5-Methyl-2 (R or S) - (2-naphthylmethyl) -3 (R) - [2-phenyl-1 (S) - (2-sulfoethylcarbamoyl) ethylcarbamoyl] hexanohydroxamic acid, sodium salt

The synthesis was carried out using the title compound of Example 25 (1) and taurine and in the same manner as in the method described in Example 15 (7) - (8).
¹ H-NMR (DMSO-d ₆₎ δ 10.15 (br s, 1H), 8.69-8.43 (br s, 1H), 8:38 (d, J = 8.7 Hz, 1H), 7.94-7.69 (m, 4H), 7.50-7.37 (m, 2H), 7.36-7.24 (m, 3H), 7.18-7.03 (m, 2H), 7.02-6.98 (m, 1H), 6.89-6.78 (m, 1H), 4.70-4.56 (m , 1H), 3.50-2.78 (m, 3H), 3.18-2.92 (m, 1H), 2.91-2.85 (m, 1H), 2.58-2.41 (m, 3H), 2.39-2.10 (m, 1H), 2.00 -1.87 (m, 1H), 1.50-1.28 (m, 2H), 0.90-0.70 (m, 1H), 0.85 (d, J = 6.3 Hz, 3H), 0.77 (d, J = 6.3 Hz, 3H).

Experimental Example 1; inhibitory Effect of the pharmaceutical on LPS in the culture supernatant of E. coli

A platinum loop of strain E. coli NIHJ JC-2 was inoculated into a test tube containing Heart Infusion Broth (HIB, 5 ml) and cultured for about 24 hours. The bacterial culture fluid was washed three times by centrifugation (3000 rpm, 15 minutes, 20 ° C, TOMY Seiko, RL-131) using 10 ml of fresh HIB medium for one wash cycle. The washed bacteria were prepared with fresh HIB medium to be about 10 ⁷ colony forming units (CFU) / ml and 0.2 ml of the prepared bacterial suspension was inoculated into an Erlenmeyer flask containing fresh HIB medium (18, 8 ml) (ie, to a final bacterial concentration of about 10 ⁵ CFU / ml). A solution (1 ml) of each compound prepared so that the concentration was 2 mM (final concentration of the compound: 100 μM) was added to the culture fluid containing the bacteria. A shaker culture at 37 ° C was carried out by means of a shaker (type RGR-1, manufactured by IWASHIYA, Ltd.), and after 24 hours, a sample of 2 ml of the culture liquid was taken. The culture fluid sample was filtered (DISMIC, 0.45 μm, Advantech Toyo) and diluted 10 ^5- fold with sterile distilled water. The resulting suspension (200 μl) was added to a Limulus reagent (LAL ES, Wako Pure Chemical Industries), and the LPS concentration was measured by means of a 37 ° C preheated toxinometer MT-285 (Wako Pure Chemical Industries).

The LPS inhibition ratio of the compound was calculated as the ratio of the LPS concentration of the group to which the compound was administered, based on the LPS concentration of the group to which the compound was not administered. As a result, the inhibition ratio of the compound of Example 1 was 46.5-65.8%. The inhibition ratio of each compound is shown in the following Table 1 as a relative ratio to the inhibition ratio of the compound of Example 1 as 1.0. Table 1: Inhibitory effect of the compound on LPS in the supernatant of an E-Coli culture Relative ratio Compound of Example 1 1.0 Compound of Example 3 0.70 Compound of Example 4 0.69 Compound of Example 5 0.80 Compound of Example 6 0.69 Compound of Example 7 0.79 Compound of Example 8 0.60 Compound of Example 9 0.51 Compound of Example 10 0.87 Compound of Example 11 0.74 Compound of Example 12 0.85 Compound of Example 13 0.87 Compound of Example 15 1.05 Compound of Example 17 0.78 Compound of Example 19 0.67 Compound of Example 21 0.79 Compound of Example 22 0.68 Compound of Example 25 0.33 Compound of Example 26 0.54

Experimental Example 2; inhibitory Effect of a pharmaceutical on LPS in the rat peritonitis model increases

A rat peritonitis (CLP) model was prepared by the method of Wichtermann et al. (J. Surg. Res. 29, 189-201 <1980>). That means a rat over Was fasted overnight, anesthetized with ether, and a median laparotomy was performed and the cecum was exposed. The cecum was ligated with a 3-O silk thread at its base and perforated twice with an 18G injection needle. The cecum was lightly squeezed to extrude feces spread on the abdomen, and the excised part was sutured. The animal was fixed in a Borrmann cage, and physiological saline or drug solution (2 mg / ml) was applied to the tail vein at an administration rate of 2.5 mg / kg / h by means of an infusion pump (22 M, Harvard, 5 ml / kg / h as dose) continuously.

After 6 hours of CLP treatment, the animal was killed with carbon dioxide. The abdominal cavity was washed by injecting phosphate buffered saline (PBS, 37 ° C, 10 ml), and the peritoneal washing fluid containing ascites (PLF) was isolated. The isolated weight of the obtained PLF was measured and PLF was centrifuged (1500 rpm for 4 minutes, 4 ° C) to isolate the supernatant. The blood drawn from the heart was centrifuged using a serum separation tube (3,000 rpm for 4 min, 4 ° C) and the serum was isolated. The LPS concentration in the abdominal cavity and in the serum was measured by means of a MT-285 (Waco Pure Chemical Industries) toxinometer preheated to 37 ° C., after the supernatant or the serum of the isolated PLF was incubated with sterile, distilled water around the 10 ⁵ 10 ^2- fold and 200 μl thereof were added to a Limulus reagent (LAL ES, Waco Pure Chemical Industries). The amount of LPS per abdominal cavity was calculated from the amount of isolated peritoneal wash fluid (PLF) × LPS concentration of PLF.

The LPS inhibition ratio of the compound was calculated as the ratio of the LPS concentration of the group to which the compound was administered to the concentration of the group to which the physiological saline was administered. The LPS inhibition ratio of each compound in blood and in the abdominal cavity was as shown in Table 2. Table 2: Inhibitory activity of the compound against an increase in LPS in the rat peritonitis model LPS inhibition ratio (%) In blood In the abdominal cavity Compound of Example 1 79.9 88.3 Compound of Example 10 81.4 88.1 Compound of Example 11 36.2 5.5 Compound of Example 13 74.2 44.7 Compound of Example 15 68.2 70.3 Compound of Example 17 59.1 14.4 Compound of Example 19 67.8 89.6 Compound of Example 21 55.9 57.1 Compound of Example 22 21.6 80.7

Out the above mentioned experimental results, it is clear that the sulfonic acid derivative of hydroxamic acid of the present invention has an LPS inhibitory effect.

Production Example 1

Tablets containing the following ingredients were prepared by a conventional method. ingredients Per tablet Compound of Example 1 10 mg lactose 125 mg corn starch 75 mg talc 4 mg magnesium stearate 1 mg total quantity 215 mg

Production Example 2

Capsules containing the following ingredients were prepared by a conventional method. ingredients Per capsule Compound of Example 1 10 mg lactose 165 mg corn starch 20 mg talc 5 mg Weight of a capsule 200 mg

Production Example 3

A suppository containing the following ingredients was prepared by a conventional method. ingredients dose Compound of Example 1 0.2 g White petrolatum 97.8 g Liquid paraffin 2 g total weight 100 g

Production Example 4

An injection containing the following ingredients was prepared by a conventional method. ingredients dose Compound of Example 1 0.2 g sodium chloride 0.9 g Distilled water for injection Appropriate amount total weight 100 g

Production Example 5

Eye drops containing the following ingredients were prepared by a conventional method. ingredients Compound of Example 1 0.1 g sodium chloride 0.3 g Sterile, purified water Appropriate amount total weight 100 g

Industrial applicability

The sulfonic acid salt of hydroxamic acid and a pharmacologically acceptable salt thereof of the present Invention have an LPS inhibitory effect and are for prophylaxis or treatment of diseases such as sepsis, MOF, rheumatoid arthritis, Crohn's disease, cachexia, myasthenia gravis, systemic lupus erythematosus, Asthma, Type I diabetes, psoriasis or other autoimmune diseases, inflammatory diseases and the like.

This application is based on the in Japanese Patent Application No. 219245/2000 and 219034/2000 ,

Claims (10)

Sulfonic acid derivative of hydroxamic acid of the formula (I)

wherein X is hydrogen or a hydroxyl group-protecting group, R ^{1 is} hydrogen, a linear or branched alkyl having 1 to 10 carbon atoms, an arylalkyl, wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms, a heteroarylalkyl, wherein the heteroaryl group a 5- or 6-membered ring group having a carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group 1 to 6 carbon atoms, a heteroarylalkylthioalkyl wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms thereof or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms and the thioalkyl group has 1 to 6 carbon atoms e has, a heteroarylthioalkyl wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused heterocyclic heteroaryl having 8 to 10 ring atoms derived therefrom, or an N-oxide thereof and the thioalkyl group has 1 to 6 carbon atoms, an arylthioalkyl wherein the aryl group has 6 to 10 carbon atoms and the thioalkyl group has 1 to 6 carbon atoms, an alkylthioalkyl wherein the alkylthio group has 1 to 10 carbon atoms and the alkyl group Has 1 to 6 carbon atoms, an arylalkylthioalkyl wherein the aryl radical has 6 to 10 carbon atoms and the alkyl radical has 1 to 6 carbon atoms and the thioalkyl radical has 1 to 6 carbon atoms, a phthaloimidoalkyl wherein the alkyl radical has 1 to 6 carbon atoms, an alkenyl with 2 to 6 carbon atoms or - (CH ₂ ) ₁ -A- [wherein l is an integer from 1 to 4 and A is a nitrogen-containing 5- or 6-membered (b) optionally, as another heteroatom, it comprises at least one kind of atom selected from nitrogen, oxygen and sulfur in a position not adjacent to the bonded nitrogen atom, (c) the hetero ring which is (a) linked through a nitrogen atom; attached nitrogen atom comprises adjacent carbon atoms, one or both of which are substituted by oxo and which (d) is benzo-fused or has one or more further carbon atoms, which are optionally substituted by a linear or branched alkyl having 1 to 6 carbon atoms or oxo, and / or which has another nitrogen atom which is optionally substituted by a linear or branched alkyl having 1 to 6 carbon atoms or phenyl], R ^{2 is} hydrogen, a linear or branched alkyl having 1 to 10 carbon atoms, an arylalkyl, wherein the aryl radical is 6 to 10 Has carbon atoms and the alkyl radical has 1 to 6 carbon atoms, a heteroarylalkyl, Where wherein the heteroaryl group is a 5- to 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof, and the alkyl group has 1 to 6 carbon atoms, a cycloalkyl having 3 to 7 carbon atoms, a cycloalkylalkyl wherein the cycloalkyl group has 3 to 7 carbon atoms and the alkyl group has 1 to 6 carbon atoms, or an aryl having 6 to 10 carbon atoms, YO, NR (wherein R ⁷ corresponds to the definition of R ² ) or S is, n is an integer from 1 to 6, R ^{3 is} hydrogen, a halogen (fluorine, chlorine, bromine, iodine), a hydroxyl group, trifluoromethyl, cyano, nitro, amino, a linear or branched alkyl having 1 to 10 carbon atoms, a linear or branched alkoxy having 1 to 6 carbon atoms, a linear or branched alkanoyloxy having 2 to 6 carbon atoms, carbamoyl, a C _1-6 -alkylamino or Di-C _{1 6} -alkylamino, R ^{4 is} OR ⁸ (wherein R ^{8 is} hydrogen, a linear or branched alkyl of 1 to 6 carbon atoms, an aryl of 6 to 10 carbon atoms, a heteroaryl selected from a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom and an N-oxide thereof, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group 1 or a heteroarylalkyl, wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms, the or is an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms) or NR ¹⁰ R ¹¹ [wherein R ¹⁰ and R ^{11 are the} same or different and each is hydrogen, a linear it or branched alkyl having 1 to 6 carbon atoms, an arylalkyl, wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms, a heteroaryl consisting of a 5- or 6-membered ring group having one carbon atom and 1 to 4 Heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, and an N-oxide thereof, a heteroarylalkyl, wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen) is an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms or an aryl Is from 6 to 10 carbon atoms or R ¹⁰ and R ¹¹ optionally together with the adjacent nitrogen atom form an optionally substituted hetero ring are] and wherein the arylalkyl, heteroarylalkyl, heteroarylalkylthioalkyl, heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl, phthaloimidoalkyl, aryl and heteroaryl, all as defined above, optionally have one or more substituents selected from a halogen, a hydroxyl group, nitro, cyano, trifluoromethyl, a C _{1 -6-} alkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, formyl, a C _2-6 alkanoyloxy, oxo, phenyl, an arylalkyl, carboxyl as defined above, a group exemplified by -COOR _a [wherein R _a is C _1-6 alkyl, one above-defined aryl alkyl or a C _6-10 aryl], carbamoyl, amino, C _1-6 alkylamino, a di-C _1-6 alkylamino, guanidino, hydroxysulfonyloxy , Arylalkyloxyalkyl wherein the arylalkyl radical is defined above and the oxyalkyl radical has 1 to 6 carbon atoms, or a pharmacologically acceptable salt thereof. A sulfonic acid derivative of hydroxamic acid according to claim 1, wherein R ^{3 is} hydrogen or a pharmacologically acceptable salt thereof. A sulfonic acid derivative of hydroxamic acid according to claim 1 or 2, wherein R ^{4 is} NHCH ₃ or NHC ₆ H ₅ , or a pharmacologically acceptable salt thereof. A sulfonic acid derivative of hydroxamic acid according to any one of claims 1 to 3, wherein R ^{1 is} phthaloimidomethyl, or a pharmacologically acceptable salt thereof. A sulfonic acid derivative of hydroxamic acid according to any one of claims 1 to 4, wherein R ^{2 is} isobutyl, or a pharmacologically acceptable salt thereof. Sulfonic acid derivative of hydroxamic acid selected from the group consisting of 5-methyl-3 (R) - [1 (S) -methylcarbamoyl-2- (4-sulfomethoxyphenyl) ethylcarbamoyl] -2 (R or S) -phthalimidomethylhexanohydroxamic acid, 5-methyl- 3 (R) - {1 (S) -methylcarbamoyl-2- [4- (2-sulfoethoxy) phenylmethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) - methylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (4 -sulfobutoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidom ethylhexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (5-sulfopentoxy) phenyl] ethylcarbamoyl} -2 (R or S) -phthalimidomethylhexanohydroxamic acid, 5-methyl-3 (R. ) - [1 (S) -methylcarbamoyl-2- (4-sulfomethoxyphenyl) ethylcarbamoyl] -2 (R or S) - (2-naphthylmethyl) hexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -methylcarbamoyl -2- (4- (2-sulfoethoxy) phenyl] ethylcarbamoyl} -2 (R or S) - (2-naphthylmethyl) hexanohydroxamic acid, 5-methyl-3 (R) - (1 (S) -methylcarbamoyl-2-) 4- (3-sulfopropoxy) phenyl] ethylcarbamoyl) -2 (R or S) - (2-naphthylmethyl) hexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (4 -sulfobutoxy) phenyl] ethylcarbamoyl} -2 (R or S) - (2-naphthylmethyl) hexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -methylcarbamoyl-2- [4- (5-sulfopentoxy) -phenyl ] ethylcarbamoyl} -2 (R or S) - (2-naphthylmethyl) hexanohydroxamic acid, 5-methyl-3 (R) - {1 (S) -phenylcarbamoyl-2- [4- (3-sulfopropoxy) phenyl] ethylcarbamoyl} - 2 (R or S) -phthalimidomethylhexanohydroxamic acid, or a pharmacologically acceptable salt thereof. Compound of the formula (III)

wherein R ^{9 is} hydrogen, a linear or branched alkyl of 1 to 10 carbon atoms, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms is a heteroarylalkyl, wherein the heteroaryl group is a 5- or 6-membered one Ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms or an aryl with 6 to 10 carbon atoms,

is a single bond or double bond, R ¹³ if

a single bond is hydrogen, an alkyl, a linear or branched alkyl of 1 to 10 carbon atoms, an arylalkyl wherein the aryl moiety has 6 to 10 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, a heteroarylalkyl wherein the heteroaryl moiety is a 5- or 5-carbon A 6-membered ring group having a carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group is 1 to 6 Has carbon atoms, a heteroarylalkylthioalkyl wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms and the thioalkyl group has 1 to 6 carbon atoms, a heteroarylthioalkyl, wherein de r heteroaryl group is a 5- to 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, or an N-oxide thereof and the thioalkyl group has 1 to 6 carbon atoms, an arylthioalkyl wherein the aryl group has 6 to 10 carbon atoms and the thioalkyl group has 1 to 6 carbon atoms, an alkylthioalkyl wherein the alkylthio group has 1 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms Arylalkylthioalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms and the thioalkyl group has 1 to 6 carbon atoms, a phthaloimidoalkyl wherein the alkyl group has 1 to 6 carbon atoms, an alkenyl having 2 to 6 carbon atoms, - (CH ₂ ) _l -A [wherein l is an integer from 1 to 4 and A is a nitrogen-containing 5- or 6-membered hetero ring which (a) is attached via a nitrogen atom andene, (b) optionally, as another heteroatom, at least one kind of atom selected from nitrogen, oxygen and sulfur in a position not adjacent to the attached nitrogen atom, (c) attached to the bonded nitrogen atom has adjacent carbon atoms, one or both thereof are substituted by oxo and the (d) is benzo-fused or has one or more further carbon atoms optionally substituted by a linear or branched alkyl of 1 to 6 carbon atoms or oxo and / or has another nitrogen atom optionally substituted by a linear or branched alkyl having 1 to 6 carbon atoms or phenyl substituted is] or -COOR ¹⁴ (wherein R ^{14 is} hydrogen, a linear or branched alkyl having 1 to 10 carbon atoms, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms, a heteroarylalkyl, wherein the heteroaryl group a 5- or 6-membered ring group having a carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, or an N-oxide thereof and the Alkyl is 1 to 6 carbon atoms or an aryl having 6 to 10 carbon atoms) or CH ₂ is when

a double bond, R ^{2 is} hydrogen, a linear or branched alkyl of 1 to 10 carbon atoms, an arylalkyl wherein the aryl radical has 6 to 10 carbon atoms and the alkyl radical has 1 to 6 carbon atoms, a heteroarylalkyl, wherein the heteroaryl radical is a 5- or 6 -linked ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms, a cycloalkyl having 3 to 7 carbon atoms, a cycloalkylalkyl wherein the cycloalkyl group has 3 to 7 carbon atoms and the alkyl group has 1 to 6 carbon atoms, or an aryl having 6 to 10 carbon atoms, YO, NR ⁷ (wherein R ^{7 is} as for R ₂ is defined) or S is, n is an integer from 1 to 6, R ^{3 is} hydrogen, a halogen (fluorine, chlorine, bromine, iodine), a hydroxyl group, trifluoromethyl, cyano, nitro, amino, a linear or branched alkyl of 1 to 10 carbon atoms, a linear or branched alkoxy of 1 to 6 carbon atoms, a linear or branched alkanoyloxy of 2 to 6 carbon atoms, carbamoyl, a C _1-5 -alkylamino or di-C _1-6 -alkylamino group and R ^{4 is} OR ⁸ (wherein R ^{8 is} hydrogen, a linear or branched alkyl of 1 to 6 carbon atoms, an aryl of 6 to 10 carbon atoms, a heteroaryl selected from a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, and an N-oxide thereof, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 Has carbon atoms, or a heteroarylalkyl, wherein the heteroaryl group is a 5- or 6-membered ring group having one carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-condensed t, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom or an N-oxide thereof and the alkyl group has 1 to 6 carbon atoms) or NR ¹⁰ R ¹¹ [wherein R ¹⁰ and R ^{11 are the} same or different and each is hydrogen, a linear or branched alkyl having 1 to 6 carbon atoms, an arylalkyl wherein the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms, a heteroaryl consisting of a 5 or 6 membered ring group having one carbon atom and 1 to 6 carbon atoms 4 heteroatoms (oxygen, sulfur or nitrogen) is selected, an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, and an N-oxide thereof, a heteroarylalkyl, wherein the heteroaryl group is a 5- or 6-membered ring group having a Is carbon atom and 1 to 4 heteroatoms (oxygen, sulfur or nitrogen), an ortho-fused, bicyclic heteroaryl having 8 to 10 ring atoms derived therefrom, or an N-oxide thereof is un d is the alkyl group having 1 to 6 carbon atoms or is an aryl having 6 to 10 carbon atoms or R ¹⁰ and R ¹¹ optionally together with the adjacent nitrogen atom form an optionally substituted hetero ring are] or a pharmacologically acceptable salt thereof. A pharmaceutical composition comprising the sulfonic acid derivative of hydroxamic acid according to one of the claims 1 to 6 or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier. LPS inhibitor comprising the sulfonic acid derivative of hydroxamic acid according to one of the claims 1 to 6 or a pharmacologically acceptable salt thereof as an active ingredient. Means for the prophylaxis or treatment of sepsis, MOF, chronic articular rheumatism, Crohn's disease, cachexia, myasthenia gravis, systemic lupus erythematosus, asthma, type I diabetes or psoriasis comprising the sulfonic acid derivative of hydroxamic acid one of the claims 1 to 6 or a pharmacologically acceptable salt thereof as an active ingredient.